Volumetric grafts for treatment of fistulae and related methods and systems

ABSTRACT

Described are devices, methods, and systems useful in the treatment of fistulae, and in certain embodiments those having openings extending into the alimentary canal, such as anorectal fistulae. Illustratively, an anorectal fistula can be treated by placing a volumetric construct within the primary opening of the fistula. In certain embodiments, the volumetric construct can include a rolled remodelable material processed to form a substantially unitary body. Advantageous such remodelable materials can include collagenous extracellular matrix materials, such as small intestine submucosa.

REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.12/793,030, filed Jun. 3, 2010, pending, which is a divisional of U.S.application Ser. No. 11/415,403, filed May 1, 2006, pending, which is acontinuation of International Application No. PCT/US2006/16748, filedApr. 29, 2006, which claims the benefit of U.S. Provisional ApplicationNo. 60/676,118, filed Apr. 29, 2005. All of the above cited applicationsare hereby incorporated by reference in their entireties.

BACKGROUND

The present invention resides generally in the field of devices andmethods useful for treating fistulae, and in a particular aspect relatesto the treatment of an anorectal fistula by filling its primary openingwith a remodelable graft material.

As further background, a variety of fistulae can occur in humans and canoccur for a variety of reasons, such as a congenital defect,inflammatory bowel disease, such as Chron's disease, irradiation,trauma, such as childbirth, or as a side effect from a surgicalprocedure. Fistulae that can occur in humans can include, for example,urethro-vaginal fistulae, vesico-vaginal fistulae, tracheo-esophagealfistulae, gastro-cutaneous fistulae, and any number of anorectalfistulae, such as recto-vaginal fistula, recto-vesical fistulae,recto-urethral fistulae, or recto-prostatic fistulae.

Anorectal fistulae can result from infection in the anal glands, whichare located around the circumference of the distal anal canal whichforms the dentate line. Approximately twenty to thirty such glands arefound in humans. Infection in an anal gland usually results in anabscess, and the abscess can then track through or around the sphinctermuscles into the perianal skin, where it can drain, either autonomouslyor via a surgical procedure. The tract that can result from the abscessis known as a fistula. The inner opening of the fistula, usually locatedat the dentate line, is known as the primary opening. The outer orexternal fistula opening is usually located in the perianal skin and isknown as the secondary opening.

Anorectal fistulae can form a variety of pathways through the perianaltissue. For example, a fistula may take a take a “straight line” pathfrom the primary to the secondary opening. This type of fistula is knownas a simple fistula. Alternatively, a fistula may form multiple tractsramifying from the primary opening and having multiple secondaryopenings. This type of fistula is known as a complex fistula.

The anatomic pathway that a fistula occupies can be classified accordingto its relationship to the anal sphincter muscles. The anal sphincterincludes two concentric bands of muscle, the inner or internal sphinctermuscle and the outer or external anal sphincter muscle. A fistula whichpasses between the inner and outer sphincter muscles is known as aninter-sphincteric fistula. A fistula that passes through both theinternal and external sphincter muscles is known as a trans-sphinctericfistula, and a fistula that passes above both sphincter muscles is knownas a supra-sphincteric fistula. A fistula that results from Crohn'sdisease usually ignores these anatomic planes, and is known as anextra-anatomic fistula.

Many complex fistulae consist of multiple tracts, some blind-ending andothers leading to multiple secondary openings. One of the most commoncomplex types of fistulae is known as a horseshoe fistula. In ahorseshoe fistula, the infection can start in an anal gland (the primaryopening) at the 12 o'clock location, for example, (with the patient inthe prone position). From this primary opening, multiple fistulae canpass bilaterally around the anal canal, in a circumferential manner.Multiple secondary openings can occur anywhere around the periphery ofthe anal canal, thereby resulting in a fistula tract with acharacteristic horseshoe configuration.

One technique for treating a perianal fistula includes excising afistula from anal tissue by making an incision adjacent the anus thatsufficiently contacts the fistula to ensure complete removal of thefistula. This surgical procedure tends to sever the fibers of the analsphincter, and may cause incontinence.

Another surgical treatment for fistulae, known as a fistulotomy,involves passing a fistula probe through the tract of a fistula in ablind manner, guiding the probe primarily with only tactile sensationand experience. After passing the probe through the fistula tract, theoverlying tissue can then be surgically divided and the fistula tractcan then be allowed to heal. Because a variable amount of sphinctermuscle can be divided during a fistulotomy, a fistulotomy may result inimpaired sphincter control, and even frank incontinence.

Yet another technique for treating fistulae involves “coring-out” thetracts of one or more fistula, such as is described in U.S. Pat. Nos.5,628,762 and 5,643,305. Unfortunately, however, these “coring-out” ofprocedures tend to make a fistula wider and more difficult to close.Additionally, the treatment of fistulae with surgical techniques, canlead to other potential complications, such as incontinence and multiplecomplex fistula formation.

In an alternative procedure, a fistula tract may be treated by insertinga seton, or a narrow diameter rubber drain through the fistula tract.The seton can be passed through the fistula tract and tied in a looparound the contained tissue and left for several weeks or months,thereby draining any infection from the area. This procedure is usuallyperformed to mature the fistula tract prior to the performance of a moredefinitive closure procedure.

More recently, treatment methods have evolved which can include theinjection of a sclerosant or a sealant, such as a collagen or fibringlue, into a fistula tract in order to block and/or close the fistula.Glues used in these procedures can be very viscous and can clog thenarrow channels of instruments used to deliver the sealants into thetract. The closure of a fistula with a sealant is usually performed as atwo-stage procedure. The first stage includes the placement of a setonin the fistula to drain any infection that is within the fistula tract.The second stage, which usually occurs several weeks after the seton isplaced, includes the injection of a suitable glue or other sealantwithin the tract of the fistula.

In view of this background, the need remains for improved andalternative techniques, devices, and systems useful for treatingfistulae, such as anorectal fistulae. Certain aspects of the presentinvention are addressed to these needs.

SUMMARY

Accordingly, in one aspect, the present invention provides for thetreatment of a fistula of the alimentary canal, such as an anorectalfistula, by filling its primary opening with a layered volumetric graftconstruct. The volumetric construct can include a rolled remodelablematerial that occupies a substantially unitary volume that can be shapedinto a configuration that enhances closure of the primary opening.

In one aspect, the present invention provides a medical graft productfor the treatment of an anorectal fistula. The medical graft product caninclude a rolled biocompatible sheet material that provides a volumetricbody configured to fill a primary opening of an anorectal fistula.

In certain embodiments of the invention, a medical graft product isprovided for the treatment of a fistula having a primary opening in thealimentary canal, a secondary opening, and a fistula tract extendingtherebetween. Such medical graft products comprise an elongate graftbody of a remodelable matrix material, the elongate graft body includingat least one generally conical longitudinal segment configured to lodgewithin and fill the primary fistula opening with remodelableextracellular matrix material. The elongate graft body is of a lengthsufficient to extend from the primary opening through the fistula tractand out the secondary opening when the generally conical segment islodged within the primary opening. The generally conical longitudinalsegment is comprised of rolled sheet-form extracellular matrix materialand thereby defines spiral layers of the sheet-form extracellular matrixmaterial. The spiral layers of sheet-form extracellular matrix materialare sufficiently compact and bonded to one another to provide thegenerally conical longitudinal segment as a substantially unitarystructure.

In yet another aspect, the present invention provides a medical graftproduct for the treatment of an alimentary (e.g. anorectal) fistula thatincludes an elongate plug. The elongate plug comprises a bioremodelablesponge form material and can occupy a volumetric shape that is adaptedfor deployment within a primary opening of the fistula.

In another aspect, the present invention provides a medical product forthe closure of an anorectal or other alimentary fistula that includes adeployment sheath and a biocompatible graft body. The biocompatiblegraft body is configured for deployment through the sheath into aprimary opening of the fistula so as to promote the closure of thefistula. Additionally, in certain aspects, the medical graft productincludes a rolled fistula plug that is preloaded into a biocompatiblesheath or cartridge that is suitable for traversing a tract of thefistula and deploying the plug for receipt in an opening of the fistula.

In still yet another aspect, the present invention provides a medicalproduct for the treatment of an anorectal or other alimentary fistulathat includes a remodelable material that occupies a volumetric shapeand has at least two regions that are formed using differential dryingtechniques. The volumetric shape can be configured to substantiallyconform to a primary opening of the fistula so as to promote the closureand the healing of the fistula. Advantageous such remodelable materialscan include extracellular matrix materials, such as mammalian smallintestine submucosa.

In yet another aspect, the present invention provides a method formaking a medical product useful for the treatment of an anorectal orother alimentary fistula. The method includes drying a rolledbiocompatible sheet material contained within a mold so as to stabilizethe material in a form configured for receipt in the fistula.

In another aspect, the present invention provides a method for treatingan anorectal or other alimentary fistula that includes locating a rolledgraft construct within a primary opening of the fistula so as to fillthe opening.

In yet another aspect, the present invention provides a medical graftproduct for treating a fistula that includes a body comprising a rolledbiocompatible sheet material providing a volumetric body configured tofill at least a portion of a fistula tract.

In another aspect, the present invention provides a medical graftproduct for the treatment of a fistula that includes a remodelablematerial having at least two regions formed by the differential dryingof the remodelable material. The material can be configured to fill andpromote the closure of the fistula opening. Advantageous suchremodelable materials can include extracellular matrix materials, suchas mammalian small intestine submucosa.

In yet another aspect, the present invention provides a fistula plugthat can include a body comprising an extracellular matrix sponge formor foam material and occupying a shape that is adapted for receipt in atleast a portion of a fistula tract.

In still yet another aspect, the present invention provides a medicalgraft product for treating a fistula that has a primary opening exposedto an alimentary canal and a fistula tract. The product comprises aporous graft body configured to lodge within and fill the primaryopening. The body has a first portion that will be closer to and be moreexposed to the alimentary canal than a second portion when the graftbody is lodged in the primary opening. The first portion is less porousthan the second portion.

In another embodiment, the present invention provides a method fortreating a fistula having a primary opening and a fistula tract. Themethod comprises contacting tissue walls defining at least a portion ofthe opening or the tract with a flowable remodelable extracellularmatrix material. In advantageous embodiments, the flowable material isdelivered so as to at least substantially fill the opening and/or atleast a portion of the fistula tract.

In another embodiment, the present invention provides a medical graftproduct useful for the treatment of a fistula having a primary opening.The medical graft product includes an elongate graft body of aresorbable matrix material, desirably a remodelable matrix material suchas a remodelable ECM. The elongate graft body includes at least onelongitudinal segment configured to lodge within and fill the primaryopening, wherein the longitudinal segment is comprised of one or morepieces of compacted sheet-form matrix material defining contacting layerportions of the sheet-form matrix material. The contacting layerportions of sheet-form matrix material are sufficiently bonded to oneanother provide the longitudinal segment as a substantially unitarystructure.

In another embodiment, the present invention provides a medical graftproduct for sealing an opening in a bodily organ or vessel, whichincludes an elongate graft body. The elongate graft body has at leastone generally conical segment configured to lodge within and fill theopening. The longitudinal segment also has one or more pieces ofcompacted sheet-form collagenous matrix material defining contactinglayer portions of the sheet-form collagenous matrix material, which arebonded to one another.

In another embodiment, the present invention provides a medical graftproduct for sealing an opening in a bodily organ or vessel that includesan elongate graft body. The elongate graft body includes at least onelongitudinal segment having a generally circular cross-section andconfigured to lodge within and fill the opening. The longitudinalsegment also includes one or more pieces of substantially randomlycompacted sheet-form collagenous matrix material that defines contactinglayer portions of the sheet-form collagenous material. The contactinglayer portions are bonded to one another.

In another embodiment, the present invention provides a method offorming an implantable graft body. The method includes providing a massof collagen-containing material to be dried to form a graft body,wherein the mass includes passages defined therein extending from asurface of the mass into the interior of the mass. The mass is thensubjected to drying conditions. In doing so, the passages can enhancethe drying process, e.g. by providing increased surface area extendinginto the interior regions of the mass that is exposed to the dryingatmosphere. In certain embodiments, the mass is a frozen hydrated mass,and the drying conditions cause the sublimation of frozen water, such asin lyophilization processes. In such processes, the exposed passagesextending into the mass can enhance the uniformity of the resultinglyophilized material. In some particular forms, methods for preparinggraft bodies comprise: (i) providing a mold retaining a mass ofcollagen-containing material; (ii) creating a plurality of passages inthe mass; (iii) hydrating the collagen-containing material mass; and(iv) drying the hydrated collagen-containing material mass in the moldwith the displaced material volumes to form a dried graft body havingdimensions generally defined by the mold. At least portions of theplurality of passages can be retained in the dried graft body. Thecollagen-containing material mass may be hydrated at any point duringthese methods, and in some forms, is hydrated before the passages arecreated. Also, in some aspects, the passages are created by displacingvolumes of material in the collagen-containing material mass by forcinga plurality of material-displacing objects, e.g., needles, into thematerial mass. The mass can then be frozen, and the needles removedleaving the passages intact. The frozen mass can then be subjected tolyophilization drying conditions.

In another embodiment, the present invention provides a medical graftproduct for treating a fistula having at least a primary opening and afistula tract. This medical graft product comprises an elongate plugbody configured to lodge within and fill at least a segment of a fistulatract. The elongate plug body is comprised of a dried collagenousmaterial and has a plurality of passages formed therein, wherein each ofthe formed passages extends from a plug body surface and into aninterior region of the plug body, e.g. partially or completely throughthe body.

In another embodiment, the present invention provides a medical graftproduct for closing a fistula tract that includes an elongate tubestructure having a body, a lumen, a proximal end, and a distal end. Theelongate tube structure has a closed distal end, includes a remodelablematerial, and is sized and configured to reside within at least asegment of a fistula tract so as to provide for the closure of thefistula tract.

In another embodiment, the present invention provides a method fortreating a fistula that includes locating a balloon within at least asegment of a fistula tract so as to facilitate closure of the fistulatract.

In another embodiment, the present invention provides a method forclosing a fistula tract that includes providing an elongate remodelableand/or resorbable balloon. The balloon is associated with a lumen of adelivery device in a fashion wherein the balloon can be filled with afill material driven through the lumen. In certain embodiments, at leasta part of the balloon, and potentially all of the balloon, resideswithin the lumen, and is configured so as to be ejected from a distalopening of the lumen when a fill material is driven into a proximalopening of the lumen. In this manner, the distal lumen opening can belocated at an opening to the fistula tract, or at some point within thefistula tract, and fill material driven through the lumen to deploy theballoon or portions thereof out of the lumen and into and along thefistula tract. In certain specific embodiments, the proximal balloon endis connected to the distal end of a delivery device, which also has alumen and a proximal end. The balloon occupies a partially or completelyinverted position within the lumen of the cannulated device. Theproximal end of the delivery device can be positioned at or within tothe primary or secondary opening of a fistula tract, and the balloon canbe deployed within the fistula tract by adding fill material into thelumen of the delivery device so as to deploy the inverted balloon orballoon portions from the lumen into the fistula tract. The balloon canbe further inflated within the fistula tract by continuing to fill theballoon with fill material to provide for the closure of the fistulatract. The present invention also provides related fistula closuresystems including the balloon and associated delivery device.

Additional aspects of the invention relate to methods for treatingfistulae which employ a medical graft product of the invention asdescribed herein.

In other embodiments, the present invention provides medical products asdiscussed herein enclosed in sterile medical packaging.

The present invention provides improved and/or alternative methods,systems, and devices for treating anorectal fistulae and other bodilyfistulae or similar undesired openings in organs or vessels. Additionalembodiments as well as features and advantages of the invention will beapparent from the further descriptions herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts an illustrative sheet form material that can be useful incertain embodiments of the present invention.

FIG. 2 depicts an illustrative sheet form material that can be useful incertain embodiments of the present invention.

FIG. 3 depicts an illustrative sheet form material that can be useful incertain embodiments of the present invention.

FIG. 4A depicts an illustrative medical graft product that can be usefulin certain embodiments of the present invention.

FIG. 4B depicts an illustrative medical graft product that can be usefulin certain embodiments of the present invention.

FIG. 5 depicts an illustrative medical graft product that can be usefulin certain embodiments of the present invention.

FIG. 6 depicts an illustrative medical graft product that can be usefulin certain embodiments of the present invention.

FIG. 7 depicts an illustrative medical graft product that can be usefulin certain embodiments of the present invention.

FIG. 8 depicts an illustrative medical graft product that can be usefulin certain embodiments of the present invention.

FIG. 9 depicts an illustrative medical graft product that can be usefulin certain embodiments of the present invention.

FIG. 10 depicts an illustrative medical graft product that can be usefulin certain embodiments of the present invention.

FIG. 11 depicts an illustrative medical graft product that can be usefulin certain embodiments of the present invention.

FIG. 12 depicts an illustrative medical graft product that can be usefulin certain embodiments of the present invention.

FIG. 13A depicts an illustrative medical graft product that can beuseful in certain embodiments of the present invention.

FIG. 13B depicts an illustrative medical graft product that can beuseful in certain embodiments of the present invention.

FIG. 14A depicts an illustrative sheet form material that can be usefulin certain embodiments of the present invention.

FIG. 14B depicts an illustrative medical graft product that can beuseful in certain embodiments of the present invention.

FIG. 15A shows a perspective view of another medical graft product ofthe invention.

FIG. 15B provides a cross-sectional view of the medical graft product ofFIG. 15A along the view line 15B-15B shown in FIG. 15A.

FIG. 16 depicts a perspective view of an illustrative medical product ofthe invention.

FIG. 17A depicts a perspective view of an illustrative medical productof the invention.

FIG. 17B depicts a cross-sectional view of the medical product depictedin FIG. 17A.

FIG. 18 depicts a perspective view of an illustrative medical product ofthe invention.

FIG. 19 depicts an illustrative grafting procedure of the invention.

FIG. 20 depicts a perspective view of an illustrative medical product ofthe invention.

FIG. 21 depicts and illustrative grafting procedure of the invention.

FIG. 22 depicts one embodiment of a graft of the invention.

FIG. 23 depicts the graft of FIG. 22 in use.

FIG. 24 depicts one embodiment of a balloon grafting apparatus of theinvention.

FIG. 25 depicts the apparatus of FIG. 24 in use.

DETAILED DESCRIPTION

For the purposes of promoting an understanding of the principles of theinvention, reference will now be made to certain embodiments thereof andspecific language will be used to describe the same. It willnevertheless be understood that no limitation of the scope of theinvention is thereby intended, such alterations, further modificationsand further applications of the principles of the invention as describedherein being contemplated as would normally occur to one skilled in theart to which the invention relates.

As disclosed above, certain embodiments of the invention provide for thetreatment of an anorectal or other bodily fistula by filling the primaryopening of the fistula with a layered volumetric construct.Additionally, the volumetric construct can include a rolled remodelablematerial that occupies a substantially unitary volume. The unitaryvolume can be shaped into a configuration that enhances the closure ofat least a primary opening of the fistula tract. In certain embodiments,a fistula plug can comprise an extracellular matrix material and caninclude certain adaptations which can enhance the deployment andsecurement of the fistula plug within a fistula tract.

Turning now to a discussion of graft materials, graft materials usefulin certain embodiments of the present invention can include any suitablebiocompatible material. Generally, the graft materials may include aremodelable material, such as a resorbable synthetic material or anaturally derived resorbable or remodelable material. Additionally,graft materials can include any other suitable naturally derived or anyother suitable nonresorbable synthetic material, or any combination ofany of the above such biocompatible materials. Such biocompatiblematerials that are at least bioresorbable will provide advantage incertain embodiments of the invention, with materials that arebioremodelable or otherwise tissue inductive so as to promote cellularinvasion and ingrowth providing particular advantage. Illustratively,remodelable materials may be used in this context to promote cellulargrowth within the graft materials to promote healing and closure of atleast the primary opening of an anorectal fistula.

Suitable materials for use in the invention can be provided bycollagenous extracellular matrix (ECM) materials, including but notlimited to those possessing biotropic or remodelable properties,including in certain forms angiogenic collagenous extracellular matrixmaterials. For example, suitable collagenous materials include ECMmaterials such as submucosa, renal capsule membrane, dermal collagen(including processed dermal collagen from human cadavers, which can beused as allograft in humans), dura mater, pericardium, facia lata,serosa, peritoneum, or basement membrane layers, including liverbasement membrane. Suitable submucosa materials for these purposesinclude, for instance, intestinal submucosa, including small intestinalsubmucosa, stomach submucosa, urinary bladder submucosa, and uterinesubmucosa. The preferred medical graft products of the invention willinclude submucosa, such as submucosa derived from a warm-bloodedvertebrate. Mammalian submucosa materials are preferred. In particular,submucosa materials derived from animals raised for meat or otherproduct production, e.g. pigs, cattle or sheep, will be advantageous.Porcine submucosa provides a particularly preferred material for use inthe present invention, especially porcine small intestine submucosa(SIS), more especially porcine small intestine submucosa retainingsubstantially its native cross-linking.

The submucosa or other ECM material can be derived from any suitableorgan or other biological structure, including for example submucosaderived from the alimentary, respiratory, intestinal, urinary or genitaltracts of warm-blooded vertebrates. Submucosa useful in the presentinvention can be obtained by harvesting such tissue sources anddelaminating the submucosa from smooth muscle layers, mucosal layers,and/or other layers occurring in the tissue source. For additionalinformation concerning submucosa useful in certain embodiments of thepresent invention, and its isolation and treatment, reference can bemade, for example, to U.S. Pat. Nos. 4,902,508, 5,554,389, 5,993,844,6,206,931, and 6,099,567.

Submucosa or other ECM materials of the present invention can be derivedfrom any suitable organ or other tissue source, usually sourcescontaining connective tissues. The ECM materials processed for use inthe invention will typically include abundant collagen, most commonlybeing constituted at least about 80% by weight collagen on a dry weightbasis. Such naturally-derived ECM materials will for the most partinclude collagen fibers that are non-randomly oriented, for instanceoccurring as generally uniaxial or multi-axial but regularly orientedfibers. When processed to retain native bioactive factors, the ECMmaterial can retain these factors interspersed as solids between, uponand/or within the collagen fibers. Particularly desirablenaturally-derived ECM materials for use in the invention will includesignificant amounts of such interspersed, non-collagenous solids thatare readily ascertainable under light microscopic examination. Suchnon-collagenous solids can constitute a significant percentage of thedry weight of the ECM material in certain inventive embodiments, forexample at least about 1%, at least about 3%, and at least about 5% byweight in various embodiments of the invention.

The submucosa or other ECM material used in the present invention mayalso exhibit an angiogenic character and thus be effective to induceangiogenesis in a host engrafted with the material. In this regard,angiogenesis is the process through which the body makes new bloodvessels to generate increased blood supply to tissues. Thus, angiogenicmaterials, when contacted with host tissues, promote or encourage theformation of new blood vessels. Methods for measuring in vivoangiogenesis in response to biomaterial implantation have recently beendeveloped. For example, one such method uses a subcutaneous implantmodel to determine the angiogenic character of a material. See, C.Heeschen et al., Nature Medicine 7 (2001), No. 7, 833-839. When combinedwith a fluorescence microangiography technique, this model can provideboth quantitative and qualitative measures of angiogenesis intobiomaterials. C. Johnson et al., Circulation Research 94 (2004), No. 2,262-268.

As prepared and used, the submucosa material or any other ECM materialmay optionally retain and/or otherwise include growth factors or otherbioactive components native to the source tissue. For example, thesubmucosa or other ECM material may retain one or more growth factorssuch as basic fibroblast growth factor (FGF-2), transforming growthfactor beta (TGF-beta), epidermal growth factor (EGF), and/or plateletderived growth factor (PDGF). As well, submucosa or other ECM materialused in certain embodiments of the invention may retain or include otherbiological materials such as heparin, heparin sulfate, hyaluronic acid,fibronectin and the like. Thus, generally speaking, the submucosa orother ECM material may retain or otherwise include a bioactive componentthat induces, directly or indirectly, a cellular response such as achange in cell morphology, proliferation, growth, protein or geneexpression. In certain preferred embodiments of the invention, the ECMmaterial will exhibit the capacity to promote angiogenesis.

Further, in addition or as an alternative to the inclusion of suchnative bioactive components, non-native bioactive components such asthose synthetically produced by recombinant technology or other methods,may be incorporated into the submucosa or other ECM material. Thesenon-native bioactive components may be naturally-derived orrecombinantly produced proteins that correspond to those nativelyoccurring in the ECM material, but perhaps of a different species (e.g.human proteins applied to collagenous ECMs from other animals, such aspigs). The non-native bioactive components may also be drug substances.Illustrative drug substances that may be incorporated into and/or ontothe ECM material can include, for example, antibiotics and/orthrombus-promoting substances such as blood clotting factors, e.g.thrombin, fibrinogen, and the like. These substances may be applied tothe ECM material as a premanufactured step, immediately prior to theprocedure (e.g. by soaking the material in a solution containing asuitable antibiotic such as cefazolin), or during or after engraftmentof the ECM material within the patient.

Submucosa or other ECM material used in certain embodiments of theinvention is preferably highly purified, for example, as described inU.S. Pat. No. 6,206,931 to Cook et al. Thus, preferred ECM material willexhibit an endotoxin level of less than about 12 endotoxin units (EU)per gram, more preferably less than about 5 EU per gram, and mostpreferably less than about 1 EU per gram. As additional preferences, thesubmucosa or other ECM material may have a bioburden of less than about1 colony forming units (CFU) per gram, more preferably less than about0.5 CFU per gram. Fungus levels are desirably similarly low, for exampleless than about 1 CFU per gram, more preferably less than about 0.5 CFUper gram. Nucleic acid levels are preferably less than about 5 μg/mg,more preferably less than about 2 μg/mg, and virus levels are preferablyless than about 50 plaque forming units (PFU) per gram, more preferablyless than about 5 PFU per gram. The ECM material used in certainembodiments of the invention is preferably disinfected with an oxidizingagent, particularly a peracid, such as peracetic acid. These andadditional properties of submucosa or other ECM materials taught in U.S.Pat. No. 6,206,931 may be characteristic of the submucosa used incertain embodiments of the present invention.

Three-dimensionally stable porous matrix materials, such as resilientfoam or sponge form materials, can be incorporated into graft constructsof the invention. Illustrative sponge or foam matrices will generallycomprise porous, three-dimensionally stable bodies formed from suitablebiocompatible matrix materials. For example, suitable biocompatiblematrix materials include naturally-occurring polymers and/or syntheticpolymers. More preferred sponge compositions of the invention willcomprise collagen as a matrix-forming material, either alone or incombination with one or more other matrix forming materials. In general,sponge matrices useful in certain embodiments of the present inventioncan be formed by providing a liquid solution or suspension of amatrix-forming material, and causing the material to form a porousthree-dimensionally stable structure; however, a sponge or foam materialcan be formed using any suitable formation method, as is known in theart.

Illustratively, in the formation of a collagenous sponge or foammaterial, a collagen solution or suspension can be prepared. Thecollagen may be derived from mammalian or other animal sources, forexample, bovine, porcine or human sources, and desirably is derived fromremodelable ECM materials as discussed herein. Synthetically-derivedcollagen may also be used. The determination of suitable collagenconcentrations in the solution will be within the purview of thoseskilled in the art, with concentration ranges of about 0.05 g/ml toabout 0.2 g/ml being typical.

Digestion of the collagen to form the collagen solution is usuallycarried out under acidic conditions, starting with ground, minced orotherwise comminuted collagen-containing tissue. Optionally, enzymaticdigestion may be utilized using known enzymes for this purpose such aspepsin, trypsin, and/or papain. After digestion, the enzymes can beremoved by suitable, known techniques.

The collagenous solution and/or suspension can be employed as a moldableor castable material in the formation of the foam or sponge. The castmaterial can be dried directly without chemical crosslinking or can becrosslinked with a suitable crosslinking agent and then dried.Illustrative crosslinking agents for these purposes includeglutaraldehyde, formaldehyde, carbodiimides, UV irradiation, or othercrosslinking agents. In preferred embodiments of the invention, thecrosslinking agent will contain polar groups that impart a hydrophiliccharacter to the final sponge matrix material. Desirably, a polyepoxidecrosslinker is utilized for this purpose, especially a polyglycidylether compound. Suitable such compounds include ethylene glycoldiglycidyl ether, available under the trade name Denacol EX810 fromNagese Chemical Co., Osaka, Japan, and glycerol polyglycidyl etheravailable under the trade name Denacol EX313 also from Nagese ChemicalCo. Typically, polyglycidyl ethers or other polyepoxide compoundsutilized in the invention will have from 2 to about 10 epoxide groupsper molecule. The use of such epoxides and/or other crosslinking agentswhich impart polar groups and a hydrophilic character to the resultingmatrix will provide for good wettability and rapid hydration andexpansion of closure devices of the invention.

Preferred sources of collagen for forming sponge matrices useful incertain embodiments of the invention include extracellular matrixmaterials such as collagenous submucosal tissues, and other collagenousbasement membrane materials. These include, for example, smallintestinal submucosa, stomach submucosa, urinary bladder submucosa,liver basement membrane, and other basement membrane materials. Foradditional information as to these collagenous matrix materials andtheir preparation, reference can be made for example to U.S. Pat. Nos.4,511,653, 4,902,508, 4,956,178, 5,554,389, and 6,099,567, andInternational Publication Nos. WO9825637 and WO9822158, each of which ishereby incorporated herein by reference in its entirety. In formingsponge matrices, these materials are preferably processed and utilizedunder conditions which retain their favorable growth properties. Thismay include, for example, processing under conditions in which nativeproteins and/or other materials, for instance biotropic agents, areretained in their bioactive form. For example, the collagen sources, andresulting sponge matrices, may include active native substances such asone or more growth factors, e.g. basic fibroblast growth factor (FGF-2);transforming growth factor beta (TGF-beta); epidermal growth factor(EFG); platelet derived growth factor (PDGF); and/or other substancessuch as glycosaminoglycans (GAGs); and/or fibronectin (FN).

Sponge matrix materials that can be used to form illustrative devices ofthe invention can be highly expandable when wetted, so as to achieve anexpanded configuration. Illustratively, expandable sponge materials canexhibit the capacity to expand at least 100% by volume, more preferablyat least about 200% by volume, and typically in the range of about 300%by volume to about 1000% by volume, when wetted to saturation withdeionized water. Sponge materials used in the invention can also exhibitadvantageous rates of expansion, achieving volume expansions as notedabove in less than about 10 seconds, more preferably less than about 5seconds, when immersed in deionized water.

Highly compact, dense sponge matrices can be prepared by first hydratingor otherwise wetting a porous sponge matrix, and then compressing anddrying the element. Such preparative processes generally provide a moredense, rigid and stably compressed sponge matrix than processes such assimple compaction of the dry sponge matrix. Drying can be conductedsufficiently to stabilize the sponge matrix. For example, preferreddrying procedures will reduce the liquid (e.g. water) content of thematrix to less than about 20% by weight, more preferably less than about10% by weight. Compression forces can be applied so as to achieve afinal density and/or desirable configuration, and can be applied in one,two or three dimensions, including radially. The drying of the compactedelement can involve lyophilization (or freeze drying) or vacuum dryingat ambient or elevated temperatures. When processed in this fashion,upon removal of the compaction force, the sponge matrix is stabilizedstructurally and remains in its highly dense and compacted state untilcontacted with a liquid susceptible to absorption by the matrix, forexample body fluids. The pores of the matrix are thereby stably retainedat a volume substantially reduced from their maximum volume, but returnto a partially or fully expanded state when the matrix material iswetted.

Compressed sponge matrices forming graft bodies of the invention can behighly dense, typically having densities of at least about 0.05 g/cm³,preferably in the range of about 0.05 g/cm³ to about 0.2 g/cm³, and morepreferably about 0.075 g/cm³ to about 0.2 g/cm³. The compacted spongematrix can have sufficient rigidity to be deployed by passage throughneedles, catheters or sheaths, for example by utilizing a push rod orother pusher element to force the sponge matrix graft body through theneedle and/or catheter cannula. Expanded sponge densities (dry) willgenerally be less than the corresponding compacted densities. Typicalexpanded densities (dry) will range from about 0.01 g/cm³ to about 0.1g/cm³, more preferably about 0.02 g/cm³ to about 0.07 g/cm³.

Compressed sponge materials may also contain agents which promotefurther retention of the compressed, high density form of the matrices.These may include for example starch, cellulose, sugars such asdextrose, or glycerin. Such agents can optionally be included in theliquid (preferably aqueous) used to hydrate or otherwise wet the spongeprior to compaction and drying. For additional information concerningfoam or sponge form materials that can be useful in certain embodimentsof the present invention, reference can be made, for example, to U.S.Pat. App. Pub. No. 2003/0013989.

In additional embodiments, fistula treatment devices of the inventioncan be made from ECM's or other collagenous materials that have beensubjected to processes that expand the materials. In certain forms, suchexpanded materials can be formed by the controlled contact of an ECMmaterial with one or more alkaline substances until the materialexpands, and the isolation of the expanded material. Illustratively, thecontacting can be sufficient to expand the ECM material to at least 120%of (i.e. 1.2 times) its original bulk volume, or in some forms to atleast about two times its original volume. Thereafter, the expandedmaterial can optionally be isolated from the alkaline medium, e.g. byneutralization and/or rinsing. The collected, expanded material can beused in any suitable manner in the preparation of a graft device.Illustratively, the expanded material can be enriched with bioactivecomponents, dried, and/or molded, etc., in the formation of a graftconstruct of a desired shape or configuration. In certain embodiments, adried graft construct formed with the expanded ECM material can behighly compressible (or expandable) such that the material can becompressed for delivery, such as from within the lumen of a cannulateddelivery device, and thereafter expand upon deployment from the deviceso as to become anchored within a patient and/or cause closure of atract within the patient.

Expanded collagenous or ECM materials can be formed by the controlledcontact of a collagenous or ECM material with an aqueous solution orother medium containing sodium hydroxide. Alkaline treatment of thematerial can cause changes in the physical structure of the materialthat in turn cause it to expand. Such changes may include denaturationof the collagen in the material. In certain embodiments, it is preferredto expand the material to at least about three, at least about four, atleast about 5, or at least about 6 or even more times its original bulkvolume. The magnitude of the expansion is related to several factors,including for instance the concentration or pH of the alkaline medium,exposure time, and temperature used in the treatment of the material tobe expanded.

ECM materials that can be processed to make expanded materials caninclude any of those disclosed herein or other suitable ECM's. Typicalsuch ECM materials will include a network of collagen fibrils havingnaturally-occurring intramolecular cross links and naturally-occurringintermolecular cross links. Upon expansion processing as describedherein, the naturally-occurring intramolecular cross links andnaturally-occurring intermolecular cross links can be retained in theprocessed collagenous matrix material sufficiently to maintain thecollagenous matrix material as an intact collagenous sheet material;however, collagen fibrils in the collagenous sheet material can bedenatured, and the collagenous sheet material can have analkaline-processed thickness that is greater than the thickness of thestarting material, for example at least 120% of the original thickness,or at least twice the original thickness.

Illustratively, the concentration of the alkaline substance fortreatment of the remodelable material can be in the range of about 0.5to about 2 M, with a concentration of about 1 M being more preferable.Additionally, the pH of the alkaline substance can in certainembodiments range from about 8 to about 14. In preferred aspects, thealkaline substance will have a pH of from about 10 to about 14, and mostpreferably of from about 12 to about 14.

In addition to concentration and pH, other factors such as temperatureand exposure time will contribute to the extent of expansion, asdiscussed above. In this respect, in certain variants, the exposure ofthe collagenous material to the alkaline substance is performed at atemperature of about 4 to about 45° C. In preferred embodiments, theexposure is performed at a temperature of about 25 to about 40° C., with37° C. being most preferred. Moreover, the exposure time can range fromat least about one minute up to about 5 hours or more. In someembodiments, the exposure time is about 1 to about 2 hours. In aparticularly preferred embodiment, the collagenous material is exposedto a 1 M solution of NaOH having a pH of 14 at a temperature of about37° C. for about 1.5 to 2 hours. Such treatment results in collagendenaturation and a substantial expansion of the remodelable material.Denaturation of the collagen matrix of the material can be observed as achange in the collagen packing characteristics of the material, forexample a substantial disruption of a tightly bound collagenous networkof the starting material. A non-expanded ECM or other collagenousmaterial can have a tightly bound collagenous network presenting asubstantially uniform, continuous surface when viewed by the naked eyeor under moderate magnification, e.g. 100×magnification. Conversely, anexpanded collagenous material can have a surface that is quitedifferent, in that the surface is not continuous but rather presentscollagen strands or bundles in many regions that are separated bysubstantial gaps in material between the strands or bundles when viewedunder the same magnification, e.g. about 100×. Consequently, an expandedcollagenous material typically appears more porous than a correspondingnon-expanded collagenous material. Moreover, in many instances, theexpanded collagenous material can be demonstrated as having increasedporosity, e.g. by measuring for an increased permeability to water orother fluid passage as compared to the non-treated starting material.The more foamy and porous structure of an expanded ECM or othercollagenous material can allow the material to be cast or otherwiseprepared into a variety of sponge or foam shapes for use in thepreparation of medical materials and devices. It can further allow forthe preparation of constructs that are highly compressible and whichexpand after compression. Such properties can be useful, for example,when the prepared graft construct is to be compressed and loaded into adeployment device (e.g. a lumen thereof) for delivery into a patient,and thereafter deployed to expand at the implant site.

After such alkaline treatments, the material can be isolated from thealkaline medium and processed for further use. Illustratively, thecollected material can be neutralized and/or rinsed with water to removethe alkalinity from the material, prior to further processing of thematerial to form a graft construct.

A starting ECM material (i.e., prior to treatment with the alkalinesubstance) can optionally include a variety of bioactive or othernon-collagenous components including, for example, growth factors,glycoproteins, glycosaminoglycans, proteoglycans, nucleic acids, andlipids. Treating the material with an alkaline substance may reduce thequantity of one, some or all of such non-collagenous componentscontained within the material. In certain embodiments, controlledtreatment of the remodelable material with an alkaline substance will besufficient to create a remodelable collagenous material which issubstantially devoid of nucleic acids and lipids, and potentially alsoof growth factors, glycoproteins, glycosaminoglycans, and proteoglycans.

In certain embodiments, one or more bioactive components, exogenous orendogenous, for example, similar to those removed from an expandedmaterial during alkaline processing, can be returned to the material.For example, an expanded material can include a collagenous materialwhich has been depleted of nucleic acids and lipids, but which has beenreplenished with growth factors, glycoproteins, glycosaminoglycans,and/or proteoglycans. These bioactive components can be returned to thematerial by any suitable method. For instance, in certain forms a tissueextract, such as is discussed in U.S. Pat. No. 6,375,989 which is herebyincorporated herein by reference in its entirety, containing thesecomponents can be prepared and applied to an expanded collagenousmaterial. In one embodiment, the expanded collagenous material can beincubated in a tissue extract for a sufficient time to allow bioactivecomponents contained therein to associate with the expanded collagenousmaterial. The tissue extract may, for example, be obtained fromnon-expanded collagenous tissue of the same type used to prepare theexpanded material. Other means for returning or introducing bioactivecomponents to an expanded remodelable collagenous material includespraying, impregnating, dipping, etc. as known in the art. By way ofexample, an expanded collagenous material may be modified by theaddition of one or more growth factors such as basic fibroblast growthfactor (FGF-2), transforming growth factor beta (TGF beta), epidermalgrowth factor (EGF), platelet derived growth factor (PDGF), and/orcartilage derived growth factor (CDGF). As well, other biologicalcomponents may be added to an expanded collagenous material, such asheparin, heparin sulfate, hyaluronic acid, fibronectin and the like.Thus, generally speaking, an expanded collagenous material may include abioactive component that induces, directly or indirectly, a cellularresponse such as a change in cell morphology, proliferation, growth,protein or gene expression.

Expanded collagenous materials can be used to prepare a wide variety offistula plug devices. Methods for preparing such plug devices caninclude contacting an ECM or other collagenous starting material with analkaline substance in an amount effective to expand the material,casting or otherwise forming the expanded collagenous material into aplug shape (e.g. one of those described herein), and lyophilizing theexpanded material to form a dried plug device

Turning now to a discussion of certain synthetic materials that can beincorporated into illustrative graft products and methods of theinvention, such synthetic materials can include nonresorbable syntheticbiocompatible polymers, such as cellulose acetate, cellulose nitrate,silicone, polyethylene teraphthalate, polyurethane, polyamide,polyester, polyorthoester, polyanhydride, polyether sulfone,polycarbonate, polypropylene, high molecular weight polyethylene,polytetrafluoroethylene, or mixtures or copolymers thereof. Illustrativeresorbable synthetic materials can include polylactic acid, polyglycolicacid or copolymers thereof, a polyanhydride, polycaprolactone,polyhydroxy-butyrate valerate, polyhydroxyalkanoate, or anotherbiodegradable polymer or mixture thereof. For further informationconcerning suitable synthetic materials (both biodegradable andnonbiodegradable), useful in certain embodiments of the presentinvention, reference can be made, for example, to U.S. Utility PatentApplication Pub. No. 2005/0228486 titled, “Implantable Frame withVariable Compliance,” filed on Apr. 11, 2005 (“Express Mail” MailingLabel No. EV 327 135 804 US), which claims priority to U.S. ProvisionalPatent Application titled, “Implantable Frame with Variable Compliance,”filed on Apr. 13, 2004. Such synthetic materials can be used to formfistula plug devices as described herein, either alone or in combinationwith ECM or other collagenous materials herein identified.

Turning now to a general discussion of medical graft products useful incertain embodiments of the invention and certain methods for making andusing the same, illustrative graft products can be formed into anysuitable volumetric shape or space-filling configuration that issuitable for promoting closure of at least a primary opening of afistula, such as an anorectal fistula. Illustratively, graft products ofthe invention can be formed by folding or rolling, or otherwiseoverlaying one or more portions of a biocompatible material, such as abiocompatible sheet material. In certain embodiments, the overlaidbiocompatible sheet material can be compressed and dried or otherwisebonded into a volumetric shape such that a substantially unitaryconstruct is formed. The substantially unitary construct can then beplaced in a fistula in a manner such that the construct fills at leastthe primary opening of the fistula, a portion of the fistula tract,and/or the secondary fistula opening.

With reference now to FIG. 1, an illustrative medical graft product canbe constructed by providing an ECM sheet material that has a trapezoidalshape 10. In certain embodiments, the sheet material 10 can include asingle ECM layer. If desirable, the single layer can be formed by fusingor otherwise bonding a plurality of smaller ECM segments or strips toform a single sheet material having a larger surface area.Illustratively, for example, suitable bonding can include compressingoverlapping areas of smaller ECM strips under dehydrating conditions.

In alternative embodiments, the ECM sheet material 10 can comprise amultilaminate ECM material. Illustratively, the multilaminate ECMmaterial can be formed by bonding a plurality of stacked and/orsubstantially overlapping ECM layers together. In certain embodiments,such multilaminate ECM materials can include from one to about ten ormore layered ECM segments, arranged or layered in a partially orcompletely overlapping manner, such as a crisscross and/or crosshatch orother suitable arrangement or pattern. Alternatively, a multilaminateECM material can include a single ECM segment that is folded or looselyrolled over itself one or more times. Optionally, an adhesive, glue, orany other suitable bonding agent, such as are discussed in more detailbelow, may be placed between ECM layers to achieve a partial or completebond. For more information concerning formation of collagenous sheetmaterial that can be useful in certain embodiments of the presentinvention, reference can be made, for example to U.S. Pat. Nos.2,127,903, 5,755,791, 5,955,110, 5,997,575, 6,206,931, and/or 6,666,892and/or International Publication No. WO96/32146, dated Oct. 17, 1996,publishing International Application No. PCT/US96/04271, filed Apr. 5,1996.

Referring now to FIGS. 2 and 3, in certain embodiments the trapezoidalECM sheet material 10 can be hydrated with a suitable hydrant, such assterilized water or saline, and rolled into a suitable volumetric shape,such as a cone for example (see FIG. 3). Illustratively, as is depictedin FIG. 2, the trapezoidal sheet material 10 can be rolled from corner12 to corner 14 along the longest base 16 of the trapezoid so as tonaturally create a conical structure with the rolled material 10 (seeFIG. 3). Additionally, in alternative embodiments, the direction of theroll can be varied in order to adjust the taper of the construct, aswell as each terminal diameter of the construct. Still further, thesheet material can be rolled around a mandrel and subsequently processedso as to impart a lumen through the graft construct, such as fordelivery of the construct over a wire guide or other elongate deliveryguide member.

Illustratively, once the sheet material 10 has been rolled, theoverlapping spirally wound layers of the sheet material 10 can be bondedtogether to form a substantially unitary medical graft product 20 (seeFIGS. 4A and 4B). Any suitable bonding technique, as is known in the artand/or discussed below can be used to unify the ECM sheet material 10.One such illustrative bonding technique can include lyophilization,which is discussed in more detail below, of the rolled sheet material10. In certain embodiments, the hydrated sheet material 10 can belyophilized while contained within a conically shaped mold or form. Themold can be sized such that it presses the layers of the spirally woundsheet material together while the material dries. Alternatively,however, the mold can be sized to only sufficiently support the sheetmaterial in a spirally wound configuration during drying, if desirable.

Additionally, in certain embodiments, the mold can include a pluralityof apertures or holes that can extend through a wall of the mold,thereby providing access to the conical cavity of the mold from anextra-atmospheric location. These apertures can serve to enhance thedrying of the rolled sheet material during the lyophilization process.Illustratively, the mold apertures can also be configured to providesurface protuberances 22 formed on the unitary graft construct 20, asare shown in FIGS. 4A and 4B (see also proturbances or nibs 22 onconstruct 10, FIG. 3), which can in turn serve to facilitate securementof the resulting graft bodies, and/or to remove epithelial cells(de-epithelialize) or otherwise abrade surfaces of the fistulaopening(s) or tracts to facilitate healing, or provide other desirablehandling characteristics. Further, in certain embodiments, the mold canbe configured to form a spool or dumb-bell type structure 24 at theproximal end of the graft construct 20. Illustratively, the spooledsection 24 can be used to assist with placement of the graft 20 within afistula tract, such as for example, by winding or otherwise attaching orlocating a string or suture within the spool 24 and thereafter using thesuture to pull the graft 20 proximally through the tract, as isdiscussed in further detail below. Additionally, in certain embodiments,the spools corresponding with the spooled section 24 can illustrativelycondition or otherwise roughen or de-epithelialize the tract tissue soas to enhance the ingrowth of patient tissue into an illustrativeremodelable graft construct.

Further, other such suitable bonding techniques can include any suitabledehydrothermal crosslinking method and/or any other suitable dryingmethod, such as evaporative cooling and/or vacuum pressing, and/or anycombination of such suitable drying methods. Additionally, bonding canoccur or be assisted by placing a suitable bonding material or agentbetween the layers of the rolled construct, such as before the sheetmaterial is rolled, for example, and/or by soaking or contacting atleast a portion of the rolled construct with a suitable bonding agent.Suitable bonding agents can include, for example, collagen gels orpastes, gelatin, or other agents including reactive monomers orpolymers, such as cyanoacrylate adhesives for example. As well, bondingcan be facilitated using chemical cross-linking agents, such asglutaraldehyde, formaldehyde, epoxides, genipin or derivatives thereof,carbodiimide compounds, polyepoxide compounds, or other similar agents.Cross-linking of ECM materials may also be catalyzed by exposing thematrix to UV radiation, by treating the collagen-based matrix withenzymes such as transglutaminase and lysyl oxidase, and byphotocrosslinking. Additionally, bonding may be achieved by combiningany two or more of the above bonding agents or methods.

Turning now to a more complete discussion of drying techniques that canbe useful in certain embodiments of the invention, lyophilization caninclude providing an ECM material that contains a sufficient amount ofhydrant such that the voids in the material matrix are filled with thehydrant. The hydrant can comprise any suitable hydrant known in the art,such as purified water or sterile saline, or any suitable combinationthereof. Illustratively, the hydrated material can be placed in afreezer until the material and hydrant are substantially in a frozen orsolid state. Thereafter, the frozen material and hydrant can be placedin a vacuum chamber and a vacuum initiated. Once at a sufficient vacuum,as is known in the art, the frozen hydrant will sublime from thematerial, thereby resulting in a dry remodelable material.

In alternative embodiments, a hydrated ECM material can be lyophilizedwithout a pre-freezing step. In these embodiments, a strong vacuum canbe applied to the hydrated material to result in a rapid evaporativecooling which freezes the hydrant within the ECM material. Thereafter,the frozen hydrant can sublime from the material thereby drying the ECMmaterial. Desirably, an ECM material that is dried via lyophilizationmaintains a substantial amount of the void space, or open matrixstructure that is characteristic of the harvested ECM material.

Drying by evaporation, or air drying, generally comprises drying apartially or completely hydrated remodelable material by allowing thehydrant to evaporate from the material. Evaporative cooling can beenhanced in a number of ways, such as by placing the material in avacuum, by blowing air over the material, by increasing the temperatureof the material, by applying a blotting material during evaporation, orby any other suitable means or any suitable combination thereof. Unlikelyophilization, the amount of void space or open matrix structure withinan ECM material is diminished during evaporative drying.

Drying by vacuum pressing generally comprises compressing a fully orpartially hydrated remodelable material while the material is subject toa vacuum. One suitable method of vacuum pressing comprises placing aremodelable material in a vacuum chamber having collapsible walls. Asthe vacuum is established, the walls collapse onto and compress thematerial until it is dry. Similar to evaporative drying, when aremodelable material is dried in a vacuum press, more of the material'sopen matrix structure is diminished or reduced than if the material wasdried by lyophilization.

Turning now to a discussion of material properties, remodelablematerials having an open matrix structure exhibit some differentmaterial properties than remodelable materials having a more diminishedor collapsed matrix structure. For example, a material having an openmatrix structure is soft and readily compliant to an implant site. Incontrast, a material having a more collapsed matrix structure tends tobe more stiff or rigid, more durable, and have greater compliance, orshape memory than a material with a more open matrix structure.Additionally, a remodelable material having a smaller pore size or morecollapsed matrix can serve to promote fluid segregation ordifferentiation between bodily cavities that are spanned by theremodelable material of diminished matrix structure.

Additionally, the rate and amount of tissue growth in and/or around aremodelable material are controlled by several factors. One such factorincludes the amount of open space available in the material's matrixstructure for the infusion and support of a patient's cell buildingcomponents, such as fibroblasts. Therefore, an open matrix structureprovides for quicker, and sometimes more, growth of patient tissue inthe remodelable material. This increased rate of patient tissue growthin the remodelable material can lead to quicker remodeling of thematerial by patient tissue.

Turning now to a discussion of differential drying methods, certaindifferential drying methods can be used to make illustrative graftconstructs that are desirably configured for placement with fistulae.These differential drying methods generally include drying a remodelablematerial, under vacuum, wherein a portion of the material contains afrozen hydrant, while other regions of the material contain hydrant inliquid form, or alternatively, frozen hydrant that is converted toliquid form during the drying process. Any suitable method or device maybe used to control the physical state of hydrant in the remodelablematerial during drying, such as, for example, a temperature controldevice, or, use of thermodynamic means, such as covering or shielding aportion of the material subject to vacuum, with a suitable shieldingmaterial, such as a material of sufficient porosity to inducedifferential drying.

Further, an illustrative fistula plug that comprises a remodelablematerial and is differentially dried can comprise at least two regionshaving differing properties and porosities. These differing regions canbe established in certain locations or comprise a certain arrangement orpattern within the remodelable fistula plug. This arrangement or patterncan be selected in order to promote or achieve any one of a number ofdesirable results, such as, for example, enhancing inter-layer bondingwithin the remodelable construct or within the sheet material used toroll the illustrative construct, differing the rate and/or ability ofpatient tissue to infiltrate or invade certain regions of a construct,increasing the compliance and/or durability of the remodelableconstruct, and/or enhancing the ability of at least a portion of thefistula plug to maintain independence between bodily cavities.Additionally, the arrangement or pattern can be selected to promote orachieve combinations of any of the previous desirable results.

In certain embodiments, differential drying can include shieldingportions or regions of a sufficiently hydrated ECM graft construct andthereafter providing a vacuum around the shielded material. Theuncovered portions of the ECM material can dry via lyophilization undervacuum, as discussed above. The shielded regions can dry over time inthese conditions as well. In these embodiments, the resulting ECMmaterial can include a dry remodelable material having a somewhat openmatrix structure that corresponds with the unshielded regions, whilehaving a more diminished or collapsed matrix structure that correspondsto the shielded regions.

It is advantageous in some differential drying techniques to performdrying operations under relatively mild temperature exposure conditionsthat can minimize deleterious effects upon the ECM materials used incertain embodiments of the invention, for example native collagenstructures and potentially bioactive substances present. Thus, dryingoperations conducted with no or substantially no duration of exposure totemperatures above human body temperature or slightly higher, say, nohigher than about 38° C., will preferably be used in some forms of thepresent invention.

Turning now to a discussion of certain medical graft products of theinvention and certain methods and systems for producing the same, withreference to FIG. 5, depicted is a fistula plug 25, formed with an ECMmaterial that can be used to block an anorectal fistula. The plug 25 caninclude a head 26 and can occupy a conical tail 28 that terminates in atruncated tip 27. Additionally, the plug 25 can have two regions ofdiffering porosity that can be created using any suitable differentialdrying technique, as discussed above. For example, as depicted in FIG.5, the head 26 of the plug 25 can occupy a region A that comprises amatrix structure that is more diminished than the matrix structure ofthe region B that corresponds to the tail 27 of the plug 25.

In an illustrative forming procedure, the depicted plug 25 can be formedby rolling or otherwise layering a hydrated ECM material into a conicalshape. Thereafter, the hydrated material can be compressed within asuitable mold having a shape that is similar to the plug 25 geometrythat is depicted in FIG. 5. In certain embodiments, the mold can havediffering regions, such as differing porosity regions, which canestablish the differing matrix regions A,B of the graft construct 25during a suitable drying and/or compression technique. Illustratively,the mold porosity of region A can be sufficient to result in thecollapse of the ECM matrix structure in region A during a suitabledrying technique. Additionally, the mold porosity of region B can besufficient to maintain the open matrix structure of the remodelablematerial during a suitable drying technique, e.g. lyophilization. Duringthe illustrative drying technique or techniques, the ECM layers candehydrothermally bond in order to provide a substantially unitaryconstruct 25, having a suitable length L, as is discussed in more below.

Illustratively, the fistula plug 25 that is depicted in FIG. 5 can beused, in certain embodiments, to fill or otherwise close an anorectalfistula. The plug can be placed such that the more diminished porosityregion A resides in the primary opening of the fistula while the moreopen porosity region B resides in at least a portion of the fistulatract. In this configuration, the diminished matrix region A can helpisolate the fistula tract from the rectum while the more open matrixregion B serves to promote more rapid closure of the fistula with itsdesirable remodeling properties.

Turning now to FIG. 6, an illustrative fistula plug that occupies acylindrical volume is shown. The depicted plug 30 can be formed byrolling a hydrated rectangular ECM sheet material and thereafterpressing and drying the construct to form a substantially unitarycylindrical construct 30. Illustratively, the spirally wound layers ofthe construct 30 can become dehydrothermally bonding during pressing anddrying of the hydrated material. Additionally, in certain embodiments,one or more cuts can be imparted to certain portions of the bondedcylindrical plug 30 that can enhance the expansive ability of the plugafter it is located within a patient and/or provide strain relief to theplug 30 in order to enhance the resistance of the plug 30 to backing outof the fistula tract after emplacement occurs. For example, certain bodymotion, such as repetitive motion (standing up/sitting down or exercise)can cause an implanted device to migrate, e.g. back out, in the absencesufficient flexibility of the overall device and/or sufficient devicefixation or anchoring. In some inventive variants, graft plugs usefulfor treating fistulas as described herein will incorporate cuts or otheradaptations along their length to provide strain relief to the plug andincrease its ability to bend or flex along its longitudinal axis under agiven load. Illustratively, the cuts can run longitudinally down theentire length of and/or only a portion of the entire length of the plug30, and/or can extend across the body of the plug 30 at any desirableangle or angles. The cuts can occupy any depth that is suitable todesirably enhance the expansion of the plug 30 within a lumen of thepatient and/or provide adequate strain relief.

With reference now to FIG. 7, a cylindrical fistula plug 35 is shownthat can be configured for use in closing or otherwise filling a bodilyfistula. As is depicted, the fistula 35 can be formed having a pluralityof protuberances or ribs 37 or other suitable anchoring or expansivemeans that can extend from the bodily surface of the plug 35. In certainembodiments, the protuberances 37 can be integral to the plug 7, such asby being imparted to the plug 7 during a bonding or drying process, froma suitable compression mold for example. Alternatively, theprotuberances 37 can be imparted to the plug 35 after the plug isformed, such as by removing or otherwise cutting suitable portions ofthe plug in order to form the protuberances. In certain embodiments, theprotuberances and intervening narrower portions of the plug along withlength can provide a volumetric plug with integrated strain relief forenhanced flexibility.

Additionally, the plug 35 can be constructed to occupy any suitablediameter and/or any suitable length to fill any suitable bodily fistula.For example, the diameter of the plug 35 can be altered by varying thecompression that is imparted to the construct during a suitable dryingprocedure and/or by varying the amount of sheet material used to formthe construct, such as by varying the overall size of the sheetmaterial, e.g. the number of turns, and/or by varying the thickness ofthe sheet material used, e.g. the number of multilaminate layers thatcan form the sheet material. Illustratively, the length of the construct35 can be varied by either appropriately sizing the sheet materialand/or trimming the construct to the desired length after inter-layerbonding is achieved, for example. In certain embodiments, the plug 35can be custom built to fit a specific fistula in a specific patient, ifdesirable.

Turning now to FIG. 8, shown is another illustrative fistula plug 40that can be useful in certain embodiments of the present invention. Theplug 40 can have a conical shape and can further include a plurality ofbulges, such as symmetrical bulges, disposed along the length of theplug 40. In certain embodiments, the bulges can occupy any suitablegeometric configuration and/or frequency and can serve to assist in thesecurement of the plug 40 within a bodily fistula. Additionally, thebulges or reliefs can be imparted or formed into the construct to such adegree to impart sufficient strain relief and flexibility to theconstruct to help resist migration after it is emplaced within apatient.

With general reference now, to FIGS. 9 through 11, a remodelable foam orsponge form material can be used in the construction of illustrativefistula plugs of the invention. As discussed above, illustrative spongeform devices will advantageously be highly expandable when wetted, so asto achieve an expanded configuration. Preferred sponge materials of theinvention will also exhibit advantageous rates of expansion, achievingvolume expansions as noted above in less than about 10 seconds, morepreferably less than about 5 seconds, when immersed in deionized water.In certain embodiments, sponge form fistula blockers or plugs may beformed individually by compaction/drying of an appropriately sizedsponge element, or they may be individually excised from a largercompacted/dried sponge matrix.

For example, in certain embodiments, illustrative graft constructshaving highly compact, dense sponge matrices can be prepared by firsthydrating or otherwise wetting a porous sponge matrix, and thencompressing and drying the element into the desired plug configurationor volumetric shape. Drying can be conducted sufficiently to stabilizethe sponge matrix. Compression forces can be applied so as to achieve afinal density and/or desirable volumetric configuration, and can beapplied in one, two or three dimensions, including radially. The dryingof the compacted element can involve lyophilization (or freeze drying)or vacuum drying at ambient or elevated temperatures. When processed inthis fashion, upon removal of the compaction force, the sponge matrix isstabilized structurally and the volumetric graft construct will remainin its highly dense and compacted state until contacted with a liquidsusceptible to absorption by the matrix, for example body fluids. Thepores of the matrix are thereby stably retained at a volumesubstantially reduced from their maximum volume, but return to apartially or fully expanded state when the matrix material is wetted.

More specifically now, with reference to FIG. 9, an illustrative graftconstruct 45 can include five sponge form spheres 42 that can beconnected to one another with a continuous suture line 44,illustratively comprising a resorbable material, that can penetrate thecenter of each sphere. Illustratively, the spheres 42 can be located atany suitable distance from one another and can occupy any suitablediameter, as is desirable to close or otherwise fill one or more fistulaopenings and/or tracts. In certain embodiments, the suture line 44 canbe secured through each sphere after each sphere is formed, usingillustrative techniques disclosed above, or, alternatively, each sphereor ball 42 can be formed around the suture 44 by locating the suture 44within each mold that can be used to form each sphere, for example.Additionally, any suitable number of spheres 42 can be used to form thegraft construct 45, and any suitable device or material can be used tounite or connect each sphere 42 of the graft construct 45. By connectingeach sponge sphere with a length of thread or other filamentousmaterial, strain relief is also imparted to the graft construct. Incertain aspects, this strain relief is desirable to help preventmigration of the device within the patient. The amount of providedstrain relief can be modified by varying the amount of length betweeneach sphere at emplacement and/or by varying the diameter and/ormaterial of construction of one or more spheres or interconnectingfilaments of the construct. Turning now to FIG. 10, another illustrativegraft construct 50 is shown. The graft construct 50 can be comprised ofECM based sponge material that is compressed within a mold having theshape of the cross-sectional view of a rope. The resulting graftconstruct 50 can be highly expansive when wetted, which can desirablyenhance the ability of the graft construct 50 to close or fill theprimary opening of a fistula. In illustrative procedures, a suitablehydrant, such as saline, may be applied or delivered to the graftconstruct 50 after it is located in a primary fistula opening to enhancethe expansion of the construct within the fistula tract. Alternatively,or additionally, a bodily fluid of the patient can sufficiently wet thelocated graft construct 50 so as to promote the expansion of theconstruct 50 within the fistula. The amount of strain relief providedwithin the device can be changed by varying the ratio of the diameter ofthe construct along its length, e.g. center of rope strand to ropestrand edges, as well as by varying the overall diameter of theconstruct.

With reference now to FIG. 11, another medical graft product 60 that canbe useful in certain embodiments of the present invention is shown.Illustratively, the medical graft product can occupy an oblong orelongated symmetrical diamond shape. The medical graft product 60 can becomprised of any suitable biocompatible material, such as a rolledsynthetic material that is bonded and compressed or pressed into thevolumetric shape depicted in FIG. 11. In alternative embodiments, themedical graft product can be formed into a shape similar to that of abow tie having a smaller center section and wider ends. Such formationcan be facilitated, if desirable, by the compressive wrapping, tying, orbonding of additional material, e.g. graft sheet material or sutures,near the longitudinal center of the device.

Turning now to further discussion concerning the securement of anillustrative fistula plug of the invention within a fistula tract, anysuitable anchoring means can be used to enhance or maintain theplacement of an illustrative fistula plug within a targeted fistulatract or portion thereof, such as the primary opening. In certainembodiments, anchoring means can include suitable barbs or otherprotuberances or ribs as are known in the art and/or as are discussedherein. As well, suitable anchoring means can include one or moresutures, in certain illustrative configurations, to anchor illustrativegraft constructs of the invention within fistulae, as is discussed infurther detail below (see text accompanying FIGS. 13A through 14B). Incertain aspects, one or more sutures can be located in either the headof the plug and/or the plug tail and securely passed through adjacentpatient tissues in order to provide for the securement of the plugwithin the tract. In additional aspects, the expansive force of theplug, e.g. a sponge form plug, can be sufficient to provide for thesecurement of the plug within at least the primary opening of the tract.

In one operative method for treating an anorectal fistula, a fistulaprobe or other elongate tracking device can be passed through a fistulatract from the secondary opening to a position outside the primaryopening in order to identify the primary opening. If desirable, ahydrogen peroxide solution can be injected through the tract from thesecondary opening to assist in finding the primary opening. After theprimary opening is identified, the fistula probe can be removed and morehydrogen peroxide solution can be injected through the tract, such as byinjecting the solution from a syringe placed at the secondary opening.Thereafter, the probe can be re-inserted within the tract and a seton orsuture can be attached to the distal end of the probe and thereafter bepulled from the primary opening through the tract and out the secondaryopening. Further irrigation can thereafter occur, if desirable, whilethe seton or thread is in place, for example. In certain aspects, theseton can then be removed and another suture can be passed through thetract from the secondary opening to the primary opening, leaving adistal suture end beyond the primary opening and a proximal suture endextending out of the secondary opening. The passage of the suture canfor example be accomplished by attaching an end of the suture to thedistal end of a fistula probe, and passing the probe from the secondaryto the primary opening). After detachment of the distal suture end fromthe probe and withdrawal of the probe, the distal end of the suture canthen be tied to the plug, e.g. around the plug body or secured through ahole adjacent the plug's leading end. Using the suture, the plug canthen be pulled through the tract from the primary opening to thesecondary opening until the plug fits snuggly within the tract. Thetrailing plug end wedged in the primary opening can then be trimmed ifneeded, and the trailing plug end can be secured to patient tissues,such as with one or more Z sutures passing through the plug and throughthe internal sphincter or other tissues at or around the location of theprimary opening. This securement at the primary opening site willdesirably also draw adjacent patient tissues over the trailing plug endto cover the same, so that no or substantially no amount of the plugremains exposed to the intestinal tract. Thereafter, the secondary plugend can be trimmed and sutured or otherwise secured to the patient,desirably also with no amounts of the plug exposed beyond the secondaryopening. It will of course be understood that many variations in such atreatment protocol can be contemplated, including for instance the useof filaments other than sutures or passed devices (e.g. forceps orprobes with gripping or other plug-engagement adaptations) to pull theplug through the primary opening and into the fistula tract. As well,these or other protocols can be adapted to pass a plug in the oppositedirection, i.e. from the secondary opening to the primary opening, to asto fill some or all of the tract and plug the primary opening. It willthus be understood that these described protocols illustrate certaintreatment methods of the invention but are not otherwise limitingthereof.

Additionally, in illustrative embodiments, one or more anchors, barbs,ribs, protuberances, and/or other suitable surface modifications can beincorporated on and/or within an illustrative plug to roughen,condition, or otherwise de-epithelialize at least a portion of thefistula tract, such as the primary opening, during and/or afteremplacement of the graft within the tract. The conditioning of the tracttissue can serve to initiate a localized healing response in patienttissue that can be advantageous in enhancing the ingrowth of patienttissue into an illustrative plug construct, such as a plug comprising anECM material. Further, in illustrative embodiments, where a suture,leader, or string is used to assist with the emplacement of anillustrative graft construct within a tract, as is discussed below, theleader can comprise an abrasive material, or comprise one or moresections and/or surface features and/or adaptations, e.g. one or morebristles that can directionally emanate from the leader material andthat can serve to roughen or otherwise condition or de-epithelializepatient tissue upon travel through and/or location within a fistulatract.

With reference now to FIG. 12, for example, illustrative anchoringand/or tissue conditioning devices 64 can be formed by locating aplurality of sutures 66 through the head portion 62 of an illustrativeconstruct 65 in a manner such that each suture end 64 extends from thesurface of the construct's head portion 62 to form a plurality ofanchoring whiskers 64. As shown, each suture end or whisker 64 can beangled in a directional manner to inhibit the head portion 62 of theconstruct from backing out of a primary fistula opening.

Additionally, in certain embodiments, whiskers or bristles 64 can belocated throughout the entire surface of the construct 65, or,alternatively, throughout only the tail portion 68 of the construct, or,still alternatively, only in certain isolated portions of the construct65. Illustratively, whiskers 64 can extend from the entire circumferenceof the construct 65, or only certain portions thereof, as well as exitthe construct's surface at any desirable angle, such as a 90 or 45degree angle, in any suitable direction (e.g. toward the head or towardthe tail). In certain embodiments, for example, a variety of whiskers 64can depart from the graft's 65 surface at a plurality of angles and/ordirections in a plurality of regions on the graft's 65 surface.Illustratively, in certain embodiments, one or more whiskers, comprisedof an absorbable or remodelable suture material, for example, can serveto provoke a sustained de-epithelialization of patient tissue after aremodelable graft is implanted, thereby enhancing the remodelablility ofthe graft, as well as the absorption or remodeling of the one or morewhiskers. For more information concerning suitable barbs and/or tissueconditioning devices that can be useful in certain embodiments of thepresent invention, reference can be made, for example, to U.S. Pat. App.Pub. Nos. 2003/0013989, 2005/0049626, 2005/0070759 and/or U.S. UtilityPatent Application titled “Implantable Graft to Close a Fistula,” filedon Jan. 21, 2005 (“Express Mail” Mailing Label No. EV 314 907 725).

Turning now to additional discussion concerning locating and deliveringillustrative medical graft constructs of the invention into or withincertain bodily fistulae, any suitable delivery method or placementtechnique can be used to locate one or more illustrative medical graftproducts within one or more bodily fistulae or portions thereof, such asat least the primary opening.

Illustratively, a plug can be located within a fistula by pulling thetail or proximal end of the plug through the primary opening in a mannersuch that the head portion or distal end of the plug fills the primaryfistula opening and the tail fills at least a portion of the fistulatract. In certain embodiments, the fistula plug can be pulled throughthe fistula tract using a fistula probe or a suitable pair of surgicalhemostats. Alternatively, an illustrative plug can be pulled through aprimary opening using a suitable leader, such as suture. In stillalternative embodiments, an illustrative plug can be deployed within afistula tract through a suitable biocompatible sheath, catheter, orneedle, optionally configured to traverse the tract of a fistula andoptionally located within the fistula tract over a suitable wire guideor under endoscopic guidance. In these embodiments, an illustrative plugconstruct can be deployed in an over the wire configuration or throughan unobstructed sheath lumen (see e.g. FIG. 16, which depicts anillustrative graft device having a central lumen for receiving wireguide).

Additionally, in illustrative embodiments, any suitable method can beused to prepare the tract, such as remove any infection and/or anyundesirable tissue or debris from the fistula tract before a medicalgraft product is deployed within the fistula. Any suitable means can beused to remove infection and/or debris, including the implantation of aseton and/or flushing the tract using a fistula probe or any othersuitable flushing means, and/or any suitable combination thereof.Suitable such flushing or tract preparation can include contacting thetract with an aqueous medium, e.g. hydrogen peroxide or saline, one ormore antibiotics or other desirable drugs, and/or one or more sclerosiveagents. For more information concerning placement of illustrativemedical constructs within fistulae and related fistulae flushing methodsand techniques, reference can be made, for example, to U.S. Pat. App.Pub. Nos. 2003/0013989, 2005/0049626, 2005/0070759 and/or U.S. UtilityPatent Application titled “Implantable Graft to Close a Fistula,” filedon Jan. 21, 2005 (“Express Mail” Mailing Label No. EV 314 907 725).

With general reference now to FIGS. 13A through 14B, shown areillustrative graft constructs of the invention that contain a stringadaptation or leader which can assist in the deployment and securementof the illustrative graft constructs. Illustratively, the string can beused as a leader that charts a pathway through a fistula in need ofclosure. For example, in certain embodiments, the string or suture canbe pulled through an anorectal fistula tract using a fistula scope, oralternatively can be pulled through the fistula tract with a previouslylocated wire guide. After the string is located within the tract, incertain embodiments, the string can be attached at any suitable locationon an illustrative fistula plug (such as the spool 24 portion of theillustrative plug construct 20 in FIGS. 4A and 4B) and can thereafter beused to pull the tail of the plug trough the primary opening, therebyfilling the primary opening with at least the head of the plug. Suchsuitable points of string attachment can include, for example, the headof the device, such as in combination with a plate that can be used todrive the plug through the tract, and/or at the tail of the device,and/or at locations that are integral to the device body, such as beingcontained within the body of the plug, such as by tracking back andforth through the body in a zigzag type fashion or pattern.

Additionally, in certain embodiments, for example, the string can firstbe used as a seton that is left in place within the fistula for a periodof time that is sufficient to drain and/or clean the fistula tract.Thereafter, the string can be tied to a fistula plug and used as aleader in an illustrative plug deployment procedure. In alternativeembodiments, a string can be attached to an illustrative plug and thenlocated within a fistula tract so as to deploy the plug within thetract, or, in yet still alternative embodiments, a string leader can beused to pull a plug into a fistula tract through a secondary opening, ifdesirable.

In illustrative embodiments, after the leader is used to sufficientlylocate a suitable plug within a tract, the string can be removed fromthe fistula plug, such as with cutting shears, for example. Inalternative embodiments, the string or suture can be made from aremodelable or otherwise resorbable material such that the string orsuture can be left in place within the fistula tract. In theseembodiments, the resorbable or remodelable leader can be used to anchorto secure the plug within the tract such as by being tied to patienttissue at any suitable location, such as a location just inside orexternal to the secondary fistula opening. Further, in alternativeembodiments, an illustrative fistula plug can be positioned within afistula tract so as to span the entire length of the tract from theprimary opening to a location external to the secondary opening. Inthese embodiments, the string or suture can be used to secure the tailof the plug to patient tissue at an external location.

More specifically now, with reference to FIG. 13A, an illustrativefistula plug 70A is shown having a head portion 72A and a tail portion74A, wherein the head portion 72A occupies a matrix structure A thatdiffers from the matrix structure B in the tail portion 74A.Additionally, the illustrative plug 70A has an indentation 76A at theproximal end of the tail that can be used, in certain embodiments, forthe attachment of a string leader 78 that can be used to pull the plug70A through a primary opening of a fistula.

Turning now to FIG. 13B, an illustrative embodiment is depicted whereinthe tail portion 74B of a graft construct 70B includes an aperture 76Bthat extends transversely through the proximal tail 74B portion of thegraft 70B. Illustratively, the aperture 76B can be used for the receiptof a suture or string 78. Additionally, the string can be passed througha fistula tract and then tied through the aperture 76B of the plug 70Bso as to provide a mechanism for locating the plug 70B within a fistulatract. After the plug is sufficiently located, the string can beremoved, by trimming the tail of the plug 70B, for example, or can beused to secure the plug within the fistula.

With reference now to FIGS. 14A and 14B, depicted is an illustrativedevice 88 of the invention that has a conical head portion 82 and anextended cylindrical tail portion 84 that is configured to extendentirely through a lengthy fistula tract from the primary opening to aposition external to the secondary opening. Additionally, theillustrative device 88 can include a leader 86 that can be used toassist in the placement of the device 88 within the tract. FIG. 14Adepicts a suitable sheet material 80 configuration that can be used toform the illustrative extended device 88. Additionally, as is shown inFIG. 14A, the leader can be incorporated within the device 88 by beingrolled within, and optionally bonded and/or compressed within, thespirally wound layers of sheet material 80. Illustratively, after theconstruct is placed within a suitable fistula, the head 82 and/or tail84 portions can be trimmed if necessary and further anchors, such as oneor more sutures can be used to secure the device 88 within the fistulaat one or more suitable locations, if desirable.

In certain embodiments, illustrative graft products can be used inconjunction with a suitable sealant or sclerosing solution which can beinjected into a fistula tract or any side branches extending from themain fistula tract. Illustratively, for example, one or more sclerosantscan be injected or otherwise placed within a tract either before or withthe emplacement of an illustrative ECM graft construct so as to initiatea healing response to promote the ingrowth of patient tissue within theremodelable graft construct. Several possible sealants are known in theart as well as discussed above, and can include fibrin glue, such asTisseal (Baxter Inc.). The glue can be prepared by mixing coagulationactivation factors with fibrinogen, which then can react to form fibrin.The fibrin can form a matrix which can serve as a scaffold for tissue ingrowth, thereby promoting the closure of the fistula tract. For moreinformation concerning the closure of branch fistulae that can be usefulin certain embodiments of the present invention, reference can be made,for example to U.S. Pat. Pub. No. 2005/0070759 and/or U.S. UtilityPatent Application titled “Implantable Graft to Close a Fistula,” filedon Jan. 21, 2005 (“Express Mail” Mailing Label No. EV 314 907 725 US).

In the event that multiple fistulae are present, an illustrative fistulagraft of the invention can be inserted into each fistula tract, untilall the primary openings are filled or otherwise closed. Identificationof each fistula tract can be made using any suitable means, such asfistuloscopy, whereby each fistula tract, as well as the primaryopening, can be accurately identified. In the event a complex fistula ispresent, a graft construct having one head and two or more tails can beinserted within the complex fistula using techniques discussed herein inorder to treat and close the complex fistula. In certain embodiments, aflowable remodelable material, as discussed below, can be used eitheralone or in conjunction with one or more graft bodies in the treatmentof a complex fistula.

Devices of the invention can be of sufficient dimension to fill at leastthe primary opening of a fistula and optionally extend to close theentire fistula tract, either alone or in combination with other similaror differing devices. In certain embodiments, the fistula plug will havea length “L” of at least about 0.20 cm, and in many situations at leastabout 1 to 20 cm (approximately 1 to 8 inches). In illustrativeembodiments, the plug will have a length of from about 2 cm to 5 cm, oralternatively, from about 2 inches to 4 inches. Additionally, in certainembodiments, fistula plugs will have a diameter of from about 0.1 mm to25 mm or more preferably from about 5 2 0 mm to 10 mm at the head of theplug, which can then taper to a tail having a diameter of from about 0.5mm to 3 mm.

Additional embodiments of the invention provide methods for treatingfistulas that involve the use of flowable remodelable extracellularmatrix material. In such embodiments, the flowable material can be usedto fill openings and/or tracts of fistulas, including anorectal or otheralimentary fistulas, and promote tissue ingrowth to close the fistulas.In this regard, the flowable material can be delivered in any suitablefashion, including for example forcible ejection from cannulated memberssuch as catheters, sheaths, or needles. Suitable flowable, remodelableECM materials for use in this aspect of the invention can be prepared,for example, as described in U.S. Pat. Nos. 5,275,826 and 5,516,533 orin International Publication No. WO2005020847 (Cook BiotechIncorporated) published Mar. 10, 2005, which are each herebyincorporated by reference in their entirety. Such flowable materials caninclude solubilized and/or particulate ECM components, and in preferredforms include ECM gels having suspended therein ECM particles, forexample having an average particle size of about 50 microns to about 500microns, more preferably about 100 microns to about 400 microns. The ECMparticulate can be added in any suitable amount relative to thesolubilized ECM components, with preferred ECM particulate to ECMsolubilized component weight ratios (based on dry solids) being about0.1:1 to about 200:1, more preferably in the range of 1:1 to about100:1. The inclusion of such ECM particulates in the ultimate gel canserve to provide additional material that can function to providebioactivity to the gel (e.g. itself including FGF-2 and/or other growthfactors or bioactive substances as discussed herein) and/or serve asscaffolding material for tissue ingrowth. Flowable ECM materials canalso be used in conjunction with graft body devices as described herein,or implant bodies having other constructions. Implanted bodies can, forexample, be provided at one or more locations of the fistula, e.g.within the primary opening, and can act as a confining barrier to anamount or bolus of flowable ECM material introduced against the barrier,such as in between two implanted graft bodies, and filling the tract ofthe fistula to promote healing.

Additionally, in certain embodiments, plug grafts of the invention canincorporate an effective amount of one or more antimicrobial agents oragents otherwise useful to inhibit the population of the graft constructor surrounding tissue with bacteria or other deleterious microorganisms.Illustrative such agents can include, for example, silver compounds,such as silver salts (e.g. silver sulfate), dextran, chitosan,chlorhexidine, and/or nitric oxide donor compounds. In illustrativeembodiments, such agents can be incorporated throughout the plug graftconstructs and/or on surfaces and/or selected regions thereof. These orother similar therapeutic agents, e.g. any drug, such as an antibiotic,can be incorporated directly on or in the graft constructs of theinvention, or they can be incorporated with a suitable binder or carriermaterial, including for instance hydrogel materials. In this regard, thegraft construct can serve to release the one or more agents over time soas to treat the tract during healing.

Additionally, in certain embodiments, illustrative graft constructs ofthe invention can be formed by randomly or regularly packing one or morepieces of single or multilayer ECM sheet material within a mold andthereafter processing the packed material. Such suitable processing caninclude, for example, providing the packed ECM sheet material in apartially or otherwise completely wetted or hydrated form and cancomplete, at least in part, by partially or completely dehydrothermallybonding the hydrated packed sheet material to establish a substantiallyunitary graft construct. Illustratively, for example, a randomly packedgraft construct can be formed by placing folded, wadded, gathered, orotherwise packed ECM sheet material within a mold, and thereafter dryingthe randomly configured material to form a substantially unitary graftconstruct. In alternative embodiments, a packed graft construct can beformed by situating randomly packed hydrated ECM material within asubstantially uniform ECM sheet material, for example a tubular orplanar sheet material lining all or part of a mold, and thereafterprocessing the configured material to form a substantially uniformconstruct. Illustratively, for example, the outer surface of the graftconstruct can be either completely or partially covered or formed usingan organized material, such as one or more layers or segments of ECMsheet material. In certain embodiments, the outer surface of a packedgraft construct, or portions thereof, can be varied, for example, byselectively covering only portions of the randomly packed or positionedmaterial with an ECM sheet material. Illustratively, a packed constructcan be formed by either partially or completely covering the innersurface of a mold with one or more wetted ECM sheet materials, andfilling the mold cavity with wadded or gathered wetted ECM material, andthereafter drying the positioned material using any suitable dryingtechnique as discussed herein.

Illustratively, wetted randomly or regularly packed ECM materials of theinvention can occupy any suitable configuration, shape, and/or length,as disclosed herein in the Figures or otherwise, and can be dried usingany suitable drying technique or any suitable combination thereof, asdisclosed herein. For example, in certain embodiments, the ECM materialcan be packed within a mold, as discussed above, and then dried withinthe mold. Alternatively, the ECM material can be packed within a moldand thereafter removed from the mold and dried. Still alternatively, apiece or pieces of ECM material can be packed within a mold, pressed orcompressed within the mold, and thereafter dried, optionally whilecontained within the mold.

Randomly packed and regularly packed graft constructs of the inventioncan be desirable for use in certain embodiments of the presentinvention. For example, illustrative randomly or regularly packed graftconstructs can have a somewhat tortuous or convoluted outer surface,depending on factors such as the amount and extent of wadding or foldingthat is present at the surface of the construct, the surface of themold, and the density of the packing. These convoluted surfaces canprovide increased surface area, which in turn, can provide additionalarea or sites for the binding or other retention of certain therapeuticagents, e.g. those disclosed herein, to the graft construct.Additionally, the overlapping material configuration that can be presentwithin the body of an illustrative packed graft construct can minimizethe number of longitudinal tissue planes that exist within the graft'sbody. Reduced longitudinal tissue planes within the construct's body candesirably reduce or prevent the flow of material through the construct,such as to enhance the independence of the rectal cavity from the softtissue of the perianal region.

Packed, molded graft constructs of the invention can also includesuitable flowable, comminuted, and/or sponge form materials, each ofwhich can be ECM based, interspersed within rolled, folded, or otherwiserandomly packed and/or covered ECM material. Additionally, thesematerials can be formed into any suitable shape, configuration, sizeand/or length as disclosed herein.

Additionally, in certain embodiments, graft constructs of the inventioncan include a hole or lumen that extends longitudinally through theconstruct, including partially or completely along the construct, suchas through the cross-sectional center of the device (see e.g. FIG. 16).Such a lumen can be formed during the processing of material, such as byrolling a wetted ECM material around a mandrel or other elongate body,processing the material to provide a substantially unitary body (e.g. bymolding and drying) and thereafter removing the mandrel or otherelongate body. Such a lumen can be created by boring the lumen from anotherwise unitary graft construct, such as with a suitable gauged needleor the like. In certain embodiments, the graft lumen can be used toassist or enhance the placement of the construct within a fistula, suchas by advancement over an elongate delivery device such as a wire guide.In alternative embodiments, the lumen can be used to contain and delivera suitable therapeutic agent, such as disclosed herein, into the fistulatract and/or surrounding tissue, such as after and/or during emplacementof the graft construct within a fistula tract. Still alternatively, sucha lumen can be used to infuse a therapeutic agent into the interstitialspaces of the graft construct, such as by plugging one end of the lumenfollowed by the infusion of the agent into and through the graftconstruct through the lumen.

In certain partial-lumen embodiments as discussed above, a plug devicecan include a longitudinal lumen that extends through only a portion ofthe device, such as beginning either at the head or tail of the deviceand exiting at a point on the outer wall of the device. Such a partiallumen can be used for receiving a wire guide. In one delivery procedure,such a plug device can track through the fistula over a previouslylocated wire guide so as to become emplaced within the patient.

In additional aspects, the present invention provides implantable graftconstructs having a plurality of passages formed or otherwise occurringtherein, wherein each of the passages includes a generally coherentpassage wall. These graft constructs may exhibit any suitable size,shape and configuration for treating fistulae or other bodily openingsor passageways, and may also be comprised of one or more of a variety ofbiocompatible materials including any of those described herein.Illustratively, an inventive construct may be comprised of acollagen-containing material (e.g., an ECM material such as porcinesmall intestine submucosa), and include an elongate body having either aconstant or varying cross-sectional area along its length, for example,a generally cylindrical elongate body or a body having a taperedportion. Also, as discussed in more detail below, some elongate graftbodies of the invention can have one or more lumens extending at leastpartially longitudinally through the bodies along their length. Whenutilized in the invention, such graft body lumens can exhibit anysuitable size, shape and configuration within the graft body, and may ormay not be in communication with one or more of the plurality ofpassages occurring in the graft body. Additionally, such a plurality ofgraft body passages may include any suitable number of individualpassages positioned randomly or non-randomly in the graft body, whereineach of these passages can exhibit any suitable size, shape andconfiguration.

Further in this regard, any passage in a graft body can extend throughall or a portion of the graft body, and in some forms, one or morepassages extends from a graft body surface and includes a generallycoherent passage wall. Illustratively, a graft body having an internallumen can have passages extending partially or entirely through a wallof the tube, e.g., from an exterior surface to an interior surface ofthe wall of material defining the lumen. Also, the spacing and size of apassage in a graft body relative to another passage in the body, as wellas the depth to which a particular passage extends into a graft body,can vary. In some forms, the passages are generally cylindrical voids,e.g. having diameters ranging from about 0.05 mm to about 15 mm, moretypically from about 0.10 mm to about 5 mm, and even more typically fromabout 0.1 mm to about 1.0 mm. These and other graft body passages usefulin the present invention can be spaced any suitable distance from oneanother, and in some embodiments, are positioned in a particular pattern(e.g., in rows), although a plurality of passages can be randomly placedas well. Further, a plurality of passages in a construct can beconfigured so that any one passage extends the same or a differentdistance into the construct relative to any other passage in theconstruct.

Inventive graft bodies having a plurality of passages occurring thereinmay be formed in any suitable manner. In some embodiments, passages canbe created in a graft body after the graft body is formed, e.g. after acast collagenous material is dried to form a coherent body. In someembodiments, at least part of the formation of some or all of thepassages in a graft body occurs during formation of the graft body.Illustratively, an inventive method can include a step where a passageis initially provided in a hydrated material mass, e.g. by displacing avolume of material in the mass. Then, with the passage(s) present in thehydrated material mass, the mass can be subjected to suitable dryingconditions (e.g., a lyophilization step) to cause or allow the passageto be retained in the dried graft body. It should be noted that ahydrated material in such processes (e.g., a reconstituted ornaturally-derived collagenous material) can have any suitable level ofhydration including full or partial hydration, and in this regard, adrying process can be used to lower starting material hydration to anysuitable level including substantially dehydrated.

A volume of material can be displaced in a hydrated mass of material tocreate passages in any suitable manner, and in certain aspects, this isaccomplished by forcing or otherwise introducing an implement or othermaterial-displacing object (e.g., a cannulated or non-cannulated needle)into the mass. Other suitable material-displacing objects can beselected according to the type of passage desired.

Additionally, these and other inventive graft body formation methods caninvolve manipulating graft material within a mold or form. It should benoted that the graft material may or may not be hydrated when placed in,on, around, etc. a mold or form. For example, in some methods, asubstantially dry ECM material (e.g., a powder or sheet material) can beplaced in a mold and then suitably hydrated for further processing. Inother methods, a hydrated starting material is placed in and/or on amold or forming structure for further processing. For example, one ormore hydrated sheets of ECM material can be applied to a form, e.g.,wrapped at least partially around a mandrel so that portions of thesheet(s) overlap. Then, the one or more sheets can be dried, and in someembodiments, dried while under compression, to form a unitary graftconstruct. In some modes of operation, a hydrated graft material isprovided within a single- or multiple-part mold having a plurality ofapertures or holes extending through a wall of the mold, therebyproviding access to the mold interior from an external location. Theseapertures can serve to enhance drying of a hydrated material during aprocessing step and in processes exerting vacuum pressure at theseapertures, can promote and/or facilitate formation of surfaceprotuberances on the graft material as portions of the same are drawntoward the apertures while under vacuum. In one aspect, an amount of ECMmaterial is retained in such a mold, and needles or othermaterial-displacing objects are inserted through some or all of the moldapertures and a distance into the ECM material, thereby displacingvolumes of the ECM material. This can be performed when the graftmaterial is hydrated, partially hydrated or dehydrated. In some forms,with needles inserted in a hydrated ECM material and providing passagestherein, the material is subjected to conditions (e.g., freezing and/ordehydrating conditions) which, alone or in combination with one or moreother conditions, cause or allow the passages to be generally retainedin the ECM material after the needles are removed.

In one embodiment, one or more sheets of hydrated ECM material aresuitably wrapped and/or randomly packed around a mandrel, and then amold having a plurality of holes extending through a wall of the mold isplaced around the material-covered mandrel, for example, so that anamount of pressure is placed on the ECM material. The mandrel can thenoptionally be removed. Thereafter, needles or other material-displacingobjects are inserted through some or all of the holes and at leastpartially through the ECM material, thereby displacing volumes of theECM material. The ECM material is then at least partially dried. In someaspects, a suitable lyophilization technique is employed, e.g., one withor without a pre-freezing step as described above. In these or otherdrying techniques in which needles or other penetrating elements are tobe left within the mass during drying, they can optionally be providedwith a plurality of apertures or holes or can otherwise be sufficientlyporous to facilitate the drying operation by allowing the passage ofgases from the wet mass. In one alternative embodiment, a hydrated ECMmaterial with emplaced needles can be subjected to freezing conditionsso that the material and any contained hydrate become substantiallyfrozen. Thereafter, the needles can be removed from the ECM material,and the remaining construct (with the frozen material passagessubstantially retaining their shape) can be placed under a vacuum sothat the frozen hydrant sublimes from the material, thereby resulting ina dry graft construct with retained passages therein.

In other modes of operation, passage-forming structures can beincorporated integrally into a mold so that passageways are formed uponintroducing the starting material in and/or on the mold. In theseaspects, the passage-forming structures can be part of the mold (e.g.,extend from a surface of the mold), or they can be separate objectsattached or otherwise coupled to the mold, to provide the desiredpassage or passages through the ultimately-formed graft body.

FIGS. 15A and 15B depict a dried, implantable graft construct 90 inaccordance with the present invention. Graft construct 90 is comprisedof an ECM material (e.g., porcine SIS), and includes an elongate graftbody 91 having a lumen 92 extending through the construct along itslength. Graft body 91 is slightly tapered toward one end, and hasmultiple passages 93 occurring therein. Passages 93 are spaced evenlyapart along the length of graft body 91, and the longitudinal axis ofeach passage runs through (and perpendicular to the longitudinal axisof) graft lumen 92 to allow communication between opposing sides of agraft body exterior surface 94. Graft body 91 also has multiple surfaceprotuberances 95 extending out from exterior surface 94.

Although not necessary to broader aspects of the invention, in someaspects, the formation of such a graft construct comprises wrapping oneor more sheets of hydrated graft material around a mandrel a number oftimes. The resulting roll of graft material is then introduced into amold, e.g. before or after withdrawing the mandrel from the roll.Thereafter, multiple material-displacing objects such as but not limitedto needles are forced through apertures in the mold and into thehydrated graft material, and the material is subjected to one or moredrying techniques such as a lyophilization process. In other aspects,the formation of such a graft construct includes placing a flowablegraft material into a mold and then subjecting the graft material tofurther processing. For example, a flowable ECM material mass, such as agel, paste or putty, potentially incorporating a particulate ECMmaterial, can be placed into a mold, and then with volumes of materialdisplaced in the mass (e.g. by penetrating needles), the ECM materialcan be dried or otherwise caused to form an integral piece to form agraft body having passages therein. Illustratively, each of the passages93 can be provided by forcing a single object through the material mass,or alternatively, where a mandrel is left in place to form alongitudinal lumen, by forcing two objects into the mass and toward oneanother from opposed directions until they abut the mandrel. The masscan then be processed to a solid graft body as discussed herein.

With reference now to FIG. 16, an illustrative fistula plug 100 isdepicted that has a central lumen 105 that extends through the plug 100along the plug's longitudinal axis. As shown, the plug 100 can have tworegions of differing porosity A, B, and the plug can occupy a generallyconical shape. In certain embodiments, region A can be less porous thanregion B, e.g. so that region A can resist penetration or wicking offluids from the rectal cavity when region A is implanted at a primaryopening of an anorectal fistula. In other embodiments, region A may bemore porous than region B, for example to enhance tissue infiltration atregion A and/or to enhance a compressible character of region A, e.g. tofacilitate healing of tissues at a primary fistula opening plugged withregion A and/or a wedging, sealing engagement of region A with a primaryfistula opening. The varied porosity of the material regions A and B canbe provided in any suitable manner, including any of those describedherein.

With general reference now to FIGS. 17 through 21, shown are additionaldevices of the present invention. In certain constructions of theillustrated devices, the structural features can provide strain reliefand longitudinal flexibility within devices so as to resist devicemigration that can be caused by stress and strain associated withpatient movement, e.g. walking, standing up/sitting down, exercise, etc.For example, FIGS. 17A and 17B depict a generally conical medicalproduct 110 having a plurality of circumferential cuts 115 in thesurface of the device, wherein the cuts are provided at spaced locationsalong the length of the device. Illustratively, the spacing, depthand/or width of each cut or of only certain cuts along the device can bevaried, e.g. every third cut, in order to enhance the amount of stressrelief that is provided by the device. In another embodiment, thecircumferential cut can be arranged as a continuous spiral cut alongsome or all of the length of the device, and the pitch, depth, and/orother features of the spiral cut can be varied to control the additionalflexibility provided to the device. Multiple, separate spiraling cutscan also be used along the length of the device to control theflexibility thereof. The cuts in these or other similar embodiments can,for example, be introduced during formation of the device body or can beimparted after its formation with a suitable tool such as a scalpel,razor blade, or other sharp cutting instrument. In certain desiredembodiments, the cuts will be effective to increase the flexibility ofthe device but will leave the device with sufficient strength andtoughness to be pushed or pulled through a fistula track withoutbreaking.

Turning now to FIG. 18, an illustrative medical device 120 is depictedthat include a plurality of e discs 125 mounted on a resorbable threador suture 127. The diameter of each disc 125 along the thread 127 cancontinuously vary such that a graft device 120 occupying a conical shapeis formed. The distance between each disc, as well as the size of eachdisc, can be varied in order to provide varying degrees of strain reliefto the device. In additional embodiments, the diameter of the discs canrandomly vary, such as by alternating between large diameters andsmaller diameters, and in certain embodiments the discs can be fusedtogether to form a unitary construct. When emplaced within a patient,the threadably attached discs can be forcibly deformed to contact oneanother within the tract so as to unify into a generally continuousgraft, or alternatively the discs in the implanted configuration canremain spaced from one another. In other device embodiments, theillustrated discs can be replaced by graft elements having othersuitable shapes, sizes and/or forms, e.g. cups, bowls, hemispheres,spheres, cones, and the like.

With reference to FIG. 19, an illustrative graft emplacement is depictedshowing an expandable plug device 130 having a plurality of bulges 132and reliefs 135 that is implanted within the primary opening of afistula tract 137. The bulges 132 and reliefs 135 can occur in agenerally symmetrical fashion along the length of the plug 130 and canserve to help secure the device within the primary opening over time.The plug device 130 can be differentially dried such that the headregion occurring at the primary opening occupies a more closed matrixstructure than the tail. The diminished porosity of the head region canprovide a separation between the alimentary canal and the fistula tract137, which will enhance the closure of the tract 137. In additionalembodiments, the tapered portions of the plug's 130 exterior surfacenear the head of the plug, or otherwise, e.g. the entire plug surface,can be coated with a suitable sealant or adhesive, e.g. a fibrin glue,in order to promote the separation of the tract from the alimentarycanal and/or help secure the plug 130 within the primary opening. Instill additional embodiments, one or more sutures can be used to anchorthe head of the plug to surrounding patient tissue to provide securementto the plug 130, or in alternative embodiments, the expandable nature ofthe plug will provide sufficient securement of the device within theprimary opening such that additional securing means, e.g. adhesive,sutures, are not required, but still may be desirable.

With reference now to FIG. 20, an illustrative device is shown thatincludes a relatively flexible remodelable or resorbable tube 140 and asuture web 142 or other pulling tether that is connected to the distalend of the tube 140 at four locations and that extends proximallythrough the tube lumen beyond the proximal end of tube 140. Inalternative embodiments, the suture web can be connected at more or lessthan four locations, can connect at any suitable location(s) along thelength of the tube, and may or may not unify at any location within orproximal to the tube lumen, including having a plurality of sutures thatseparately extend from the proximal end of the tube. As shown in FIG.21, the tube 140 can be located within a fistula tract and the sutureweb 142 can thereafter be pulled (from an external location) in aproximal direction so as to collapse and gather or bunch the distal endof the tube within the primary opening 147 of the fistula tract so as toclose the primary opening. In this regard, the wall thickness of thetube can be varied in order to vary the collapse/gather characteristicsof the graft material at the primary opening. For example, the tube maybe a solid cylindrical device having a relatively small lumentherethrough for receiving the suture or other tether, thus providingmore abundant material to gather within the primary opening when thetether is pulled. In illustrative embodiments, the distal end of thetube can be sutured to patient tissue, and the thread and proximal tubeend can be trimmed and optionally secured to the patient. The flexiblenature of the tube will allow the tube to collapse and gather within theprimary opening 147, potentially in a fashion which effectively sealsthe tube 140 at the primary opening. In certain embodiments, one or moretherapeutic agents can be introduced into the lumen of the implantedtube and/or additional graft material, such as a flowable graftmaterial, can be placed within the lumen so as to enhance the closure ofthe tract. In alternative embodiments, the tube lumen extending alongthe fistula tract can be left open and can serve to facilitate drainageof the lumen during healing. In still further alternative embodiments afistula closure device with an actuatable end can include an elongatebody (e.g. cylinder) of graft material having alongitudinally-collapsible distal region and an internal or externaltether attached to the distal region and extending proximally along thebody and configured such that pulling the tether in the proximaldirection collapses the distal region, causing an enlarged diameterthereof. Illustratively, FIG. 22 provides a perspective view of a graftdevice 150 including a plug body 151 having collapsible distal region152 and an internal pull tether 153. Internal pull tether 153 hasmultiple distal attachment portions 154 exiting the distal end 155 ofbody 151 and engaged at distributed locations on distal end 155, forinstance with knots as shown. Other engagement members such as beads,discs, clips, etc., desirably resorbable, can also be used. Pull tether153 extends through the body 151 and exits proximal end 156 thereof. Asillustrated in FIG. 23, when implanted within a fistula tract withcollapsible region 152 near, at or beyond a primary opening thereof,tether 153 can be pulled to collapse distal region 152 and cause anexpanded diameter thereof that can lodge within, or can be positioned tolodge within, the primary opening. The distal and proximal ends of thedevice 150 can then be secured to patient tissue by suturing or othertechniques if desired, as described herein.

In certain aspects, fistula plug devices can include elongate tubularballoon structures which can be placed within at least the primaryopening of the fistula so as to provide for the closure of the fistula.Such elongate tube structures can have a closed distal end, a lumen, andan open proximal end. The distal end of the tube structure can reside inthe secondary opening, but it will typically be more desirable to locatethe closed distal end within the primary opening of the fistula tract.In certain aspects, the elongate tubular structure can be expandablewith a fill material so as to expand within the fistula and provideclosure thereof. Such expandable constructs include both single walledand double walled balloon devices. Such double walled balloon devicesgenerally contain two lumens. The first lumen is defined by the outerballoon wall and the inner balloon wall, and the second lumen is definedby the inner balloon wall. Additionally, the elongate tube structure caninclude a remodelable material and can be filled or inflated with aremodelable fill material, such that the patient's tissue remodels thedevice and fill material to enhance the closure of the fistula tract.

Turning now to a discussion of elongate tube materials, any suitablebiocompatible material can be used to form the tube, as are discussedherein, such as remodelable materials, e.g. absorbable synthetics orextracellular matrix materials, or non-absorbable synthetic materials,including those described herein. In certain aspects, suitable elongatetube materials can be obtained by isolating tubular or pouch form ECMmaterials, such as, for example, small stomachs, urinary bladders,vascular vessels, ureters, and/or suitable portions of thegastrointestinal (GI) tract. Other suitable elongate tube or balloonmaterials may include substantially non-antigenic elastic materials. Foradditional information as to suitable balloon materials that can be usedin the present invention, reference can be made, for example, to U.S.Pat. Nos. 4,819,637, 5,222,970, 5,304,123, 5,411,475, 5,779,672, and/or5,830,228 each of which is hereby incorporated by reference in itsentirety.

The elongate tube may include one or more radiopaque and/or ecogenicmarkers or a radiopaque coating or impregnation to assist invisualization of the material during a non-invasive procedure. Forexample, radiopaque substances containing tantalum, barium, iodine, orbismuth, e.g. in powder form, can be coated upon or incorporated withinthe ECM or other remodelable material, such that, for example, thelocation of the balloon's distal end is detectable.

Turning now to a discussion of inventive fill materials that can be usedin conjunction with balloons or other fillable devices, the device canbe filled with any material conducive to achieving closure of a fistulaof interest. In this regard, the fill material may be a solid, liquid,gel, or foam, such as blood, polymer, contrast medium, a remodelable orbioabsorbable material, saline, a non-bioabsorbable material, collagenrods or particulates, a collagenous or gelatinous foam, air, chitosan,gelatin, oxidized regenerated cellulose, calcium alginate, alginate,thrombin-fibrin enhanced materials, fibrin glues, or any suitablecombination thereof.

In one embodiment, the fill material can comprise a comminuted,flowable, (e.g. fluidized), and/or gel form material, as discussedherein. Such fill material can include one or more agents for contactingthe fistula tract through pores or apertures present in the elongatetube. Illustrative such agents include sclerosive agents, aqueous basedagents, e.g. hydrogen peroxide or saline, antibiotics, or any suitablecombination thereof. Alternatively, the fill material can comprise asuitable solidifying polymer, such as a polymer of 2-hydroxyethylmethacrylate (HEMA). Upon addition of a catalyst to HEMA at a certaintemperature, HEMA will gradually change from a liquid form to either agelatinous or solid form over approximately twenty minutes. This changein form is desirable in a fill material because the material can easilyflow into the elongate tube device, eliminating void space between thedevice and patient tissue, and then solidify, thereby enhancing theclosure of the fistula. For more information on HEMA and other fillmaterials useful in embodiments of the present invention, reference canbe made, for example, to U.S. Pat. Nos. 4,819,637, 5,222,970, 5,304,123,5,411,475, and/or 5,830,228, each of which is hereby incorporated hereinin its entirety.

Additionally, the fill material, including, e.g. remodelable ECM fillmaterials, can include one or more radiopaque and/or ecogenic markers ora radiopaque coating or impregnation to assist in visualization of thematerial during a non-invasive procedure. For example, radiopaquesubstances containing tantalum, barium, iodine, or bismuth, e.g. inpowder form, can be coated upon or incorporated within a fill material,such that, for example, the location of the fill material within apatient's body can be detected.

Elongate tube devices can have sufficient length to reside within theentire fistula tract, or only a portion thereof. Illustrative suchlengths can typically range from about 0.5 cm to about 20 cm. Suchlengths can often range from at least about 1 cm in length to about 10cm in length. Further, an elongate tube device can be provided to aphysician in a relatively long length and the physician can thereaftercut the device down to fit the length of the desired fistula tract.Illustrative such elongate tube structures can have maximum expandeddiameters that range from about 1 mm to about 25 or more mm. In certainembodiments the diameter of the tube can be relatively constant alongthe tube. In certain other embodiments the tube diameter can vary alongthe length of the tube, such as to provide a device having a distal endthat is wider than the proximal end. Such a device can provide a taperedregion and optionally a continuous taper in a direction from the distaldevice end to the proximal device end so as to occupy a conical shape.For example, in certain forms the distal tube end can have a maximumexpanded diameter of about 1-20 mm and the tail can have a maximumexpanded diameter of about 0.1 to 5 mm. In additional embodiments, thedistal maximum expanded diameter of the balloon can be such that a bulbis formed at the distal end of the device. Optionally, the bulbed devicecan thereafter continually taper down to the proximal tube end.Illustratively, the maximum expanded tube diameter can vary in anysuitable manner along its length to provide a plurality of balloonshapes, e.g. bow tie shapes, elongate diamond shapes, and the like.

Such elongate tube devices can be delivered within the fistula using anysuitable technique as discussed herein or otherwise. In certainembodiments, the elongate tube can be received over an elongate device,such as a fistula probe, pusher, or sheath, and thereafter be locatedwithin a fistula tract by moving the elongate device through the tractfrom the secondary opening to the primary opening so as to push the tubethrough the tract. After the device is located within the tract, it canoptionally be filled or inflated using a suitable fill material asdiscussed herein. Fill can be added using any suitable technique ordevice, such as a syringe containing fill material. The fill materialcan be placed into the elongate tube directly from the syringe, oralternatively, the syringe can be hooked to a suitable cannulateddevice, such as a sheath or needle, and the fill material can flowthrough the device and into the elongate tube.

In one delivery mode for a tube graft device, a sheath can be placedwithin a fistula tract and the elongate tube can be placed within thesheath. The tube can be placed within the sheath before or after thesheath is located within the fistula. The sheath and balloon can beplaced within the tract via either an approach from the secondaryopening or an approach from the primary opening. Optionally, the sheathand/or tube can be emplaced with the assistance of a previously locatedwire guide.

In certain embodiments of the invention, a treatment system includes anelongate fillable balloon having a balloon opening associated with alumen of a delivery device for delivering a fill material into theballoon. The delivery device can, for example, be a syringe having anoutlet tube, or a catheter, sheath or similar cannulated device throughwhich a fill material can be passed. In desirable embodiments, theballoon is received at least partially and potentially completely withinthe lumen of the fill material-delivery device, for example in agathered and/or inverted configuration, and is partially or completelydeployable from a distal lumen opening of the device upon passing a fillmaterial into a proximal lumen opening of the device. For instance, thematerial defining the balloon opening can be secured to the exterior ofthe delivery device tube at or proximate to the distal end thereof, orto the walls of the delivery device lumen, leaving the balloon openingin an open position for receiving fill material passed through thedelivery device lumen. As one illustrative embodiment, FIG. 24 showsballoon delivery apparatus 160 including a remodelable or resorbableballoon graft 161 having a proximal end 162 connected to the distal end163 of a cannulated device 164, such as a sheath, having an internallumen 165. A portion of the balloon graft 161 can be inverted withinitself, and in certain embodiments, the bulk of the balloon 161 body,including the distal end 166, can be located within the sheath lumen.The distal end 163 of the cannulated device 164 can then be placed at(or within) the primary or secondary opening of a fistula tract, such asa fistula tract that has been prepared by one or more flushes ofsuitable solution, e.g. hydrogen peroxide. Thereafter, the balloon canbe deployed within the fistula tract using any suitable technique toevert or deploy the balloon from the lumen of the sheath. One suchtechnique includes the use of a rod or other elongate pusher element tomove the balloon from the sheath lumen and extend it within the fistulatract. Alternatively or additionally, a fill material, such as aflowable remodelable or resorbable material can be passed distallythrough the lumen 165, such as by mounting a syringe containing fillmaterial on the proximal end 167 of the cannulated device 164 with aluer lock system. Fill material can be forcibly added through the lumen165 in a fashion that causes the balloon to eject from the distal endand elongate into and through a fistula tract 168 (see FIG. 25). Thefilling can be continued until the tube is sufficiently filled withinthe fistula tract so as to cause closure thereof. In certainembodiments, fill material can be added to the elongate balloon graftstructure on more than one occasion, if desirable, such as duringfollow-up office visits.

Once the elongate tube is sufficiently emplaced within the tract, theproximal tube end can be closed. Illustrative closure devices ortechniques, include tying off the tube and/or securing a closed tube endwith fasteners, clips, absorbable sutures, and/or elastic cuffs. Inpreferred embodiments, the closure device or material will be at leastabsorbable, if not remodelable. As part of the closure process, theproximal tube end can be trimmed and optionally secured to patienttissue. The distal tube end can also be secured to patient tissue usingany suitable technique discussed herein. In additional aspects, the tubecan include one or more protuberances, barbs, and/or anchors, such asalong its body to provide migration resistance to the device. For moreinformation regarding inflatable tube devices that can be adapted to anduseful in certain embodiments of the present invention, reference can bemade, for example, to U.S. patent application Ser. No. 11/294,998,entitled “Inflatable Occlusion Devices, Methods, and Systems, filed onDec. 6, 2005 and/or U.S. patent application Ser. No. 11/322,145,entitled “Inverting Occlusion Devices, Methods, and Systems, filed onDec. 29, 2005, each of which is incorporated herein by reference.

The invention also provides medical kits that include graft devices ofthe invention sealed within medical packaging potentially in combinationwith other components, for example including one or more of a sheath, aguidewire, a fistula probe, etc. The final, packaged products areprovided in a sterile condition. This may be achieved, for example, bygamma, e-beam or other irradiation techniques, ethylene oxide gas, orany other suitable sterilization technique, and the materials and otherproperties of the medical packaging will be selected accordingly.

All publications cited herein are hereby incorporated by reference intheir entirety as if each had been individually incorporated byreference and fully set forth.

The use of the terms “a” and “an” and “the” and similar references inthe context of describing the invention (especially in the context ofthe following claims) are to be construed to cover both the singular andthe plural, unless otherwise indicated herein or clearly contradicted bycontext. Recitation of ranges of values herein are merely intended toserve as a shorthand method of referring individually to each separatevalue falling within the range, unless otherwise indicated herein, andeach separate value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein, isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention unless otherwise claimed. Nolanguage in the specification should be construed as indicating anynon-claimed element as essential to the practice of the invention.

While the invention has been illustrated and described in detail in thedrawings and foregoing description, the same is to be considered asillustrative and not restrictive in character, it being understood thatonly the preferred embodiments have been shown and described and thatall changes and modifications that come within the spirit of theinvention are desired to be protected.

1. A method of forming an implantable graft body, comprising: providinga mold retaining a mass of a hydrated collagen-containing material;inserting a plurality of material-displacing objects into the hydratedmass through openings in a side wall of the mold; subjecting thehydrated mass to freezing conditions so as to form a frozen masscontaining frozen water with the material-displacing objects remaininginserted in the frozen mass; removing the material-displacing objectsfrom the frozen mass; and subjecting the frozen mass to dryingconditions so as to cause sublimation of the frozen water.
 2. The methodof claim 1, wherein said inserting is effective to form a plurality ofelongate generally cylindrical passages extending from an exteriorsurface of the hydrated mass into interior regions of the hydrated mass.3. The method of claim 2, wherein the generally cylindrical passages areretained following sublimation of the frozen water, each of the retainedpassages having a generally coherent passage wall.
 4. The method ofclaim 1, wherein the collagen-containing material comprises acollagenous sheet material.
 5. The method of claim 1, wherein thecollagen-containing material comprises a remodelable extracellularmatrix sheet material obtained in sheet form from a collagenous tissuesource, the remodelable extracellular matrix sheet material effective tostimulate cellular invasion and ingrowth into the remodelableextracellular matrix sheet material upon implantation in the body of apatient.
 6. The method of claim 5, wherein the remodelable extracellularmatrix sheet material comprises submucosa, dura mater, pericardium,basement membrane, or dermal collagen.
 7. The method of claim 5, whereinthe remodelable extracellular matrix sheet material comprises a rolledsheet.
 8. A method of forming an implantable graft body, comprising:providing a mass of collagen-containing material to be dried in theformation of the graft body, wherein volumes of material are displacedin the mass so as to provide a plurality of passages in the massextending from a surface of the mass into an interior of the mass; andsubjecting the mass to drying conditions.
 9. The method of claim 8,further comprising: providing a mold retaining said mass ofcollagen-containing material, wherein the mass is subjected to saiddrying conditions in the mold so as to form a dried graft body havingdimensions generally defined by the mold.
 10. The method of claim 9,wherein the collagen-containing material comprises one or more pieces ofan extracellular matrix sheet material compressed within the mold. 11.The method of claim 8, wherein the plurality of passages includes aplurality of elongate generally cylindrical passages.
 12. A method offorming an implantable graft body, comprising: providing a hydrated massof collagen-containing material, wherein volumes of material aredisplaced in the hydrated mass so as to form a plurality of passagesextending into interior regions of the hydrated mass; and subjecting thehydrated mass to lyophilization conditions, wherein said plurality ofpassages are sufficient to provide an increased exposed surface areaextending into the interior regions of the hydrated mass such that thecollagen-containing material in the hydrated mass becomes substantiallyuniformly lyophilized.
 13. The method of claim 12, wherein saidplurality of passages includes elongate generally cylindrical voidshaving diameters ranging from about 0.05 mm to about 15 mm.
 14. Themethod of claim 12, wherein the mass of collagen-containing material isa molded construct.
 15. A method of forming an implantable graft body,comprising: providing a hydrated mass of collagen-containing material;inserting a plurality of generally cylindrical needles into the hydratedmass so as to form a corresponding plurality of elongate generallycylindrical voids around the needles in the hydrated mass; subjectingthe hydrated mass to drying conditions so as to form a dried graft bodyin which the elongate generally cylindrical voids are retained in thedried graft body.
 16. The method of claim 15, wherein the elongategenerally cylindrical voids extend from an exterior surface of the driedgraft body into interior regions of the dried graft body, the elongatecylindrical voids having diameters ranging from about 0.05 mm to about15 mm.
 17. The method of claim 16, wherein said dried graft bodycomprises one or more pieces of compacted sheet-form remodelableextracellular matrix material defining contacting layer portions of thesheet-form extracellular matrix material, and wherein said contactinglayers portions of sheet-form extracellular matrix material aresufficiently bonded to one another to provide the dried graft body as asubstantially unitary structure.
 18. A method for making a medicalproduct for the treatment of a fistula, comprising: providing a moldcontaining a hydrated biocompatible sheet material, wherein thebiocompatible sheet material comprises a rolled sheet; and drying thesheet material in the mold so as to form a dried graft body havingdimensions generally defined by the mold, wherein volumes of materialare displaced in the rolled sheet during said drying so as form aplurality of passages extending into interior regions of the driedgraft.
 19. The method of claim 18, wherein the biocompatible sheetmaterial comprises an extracellular matrix material.
 20. A medical graftproduct for treating a fistula, comprising: a molded graft constructcomprising one or more pieces of sheet-form collagenous extracellularmatrix material defining contacting layer portions of the sheet-formcollagenous extracellular matrix material, wherein said contacting layerportions of the sheet-form collagenous extracellular matrix material aresufficiently dehydrothermally bonded to one another to provide saidgraft construct as a substantially unitary structure.
 21. The medicalgraft product of claim 20, wherein said one or more pieces of sheet-formcollagenous extracellular matrix material are substantially dried. 22.The medical graft product of claim 20, wherein said one or more piecesof sheet-form collagenous extracellular matrix material comprise arolled sheet.
 23. The medical graft product of claim 22, wherein saidmolded graft construct includes a generally conical longitudinalsegment.
 24. The medical graft product of claim 20, wherein said moldedgraft construct has a plurality of passages formed therein with eachformed passage including a generally coherent passage wall that extendsfrom an exterior surface of the molded graft construct into interiorregions of the molded graft construct.
 25. The medical graft product ofclaim 24, wherein said plurality of passages includes a plurality ofelongate cylindrical voids.
 26. The medical graft product of claim 25,wherein the elongate cylindrical voids have diameters ranging from about0.10 mm to about 5 mm.
 27. The medical graft product of claim 24,wherein said one or more pieces of sheet-form collagenous extracellularmatrix material includes lyophilized collagenous material with saidplurality of passages including a plurality of generally cylindricalpassages being sufficient to provide an increased exposed surface areaextending into the interior regions of the molded graft construct suchthat the lyophilized collagenous material in the molded graft constructis substantially uniformly lyophilized.
 28. A method for making amedical graft product useful for treating a fistula, comprising:providing a molded construct comprising one or more pieces of sheet-formextracellular matrix material, said sheet-form extracellular matrixmaterial being in a hydrated condition and defining contacting layerportions of the sheet-form extracellular matrix material; and drying themolded construct such that the contacting layer portions of thesheet-form extracellular matrix material become dehydrothermally bondedto one another to provide said molded construct as a substantiallyunitary graft structure.
 29. The method of claim 28, wherein said dryingoccurs with the one or more pieces of sheet-form extracellular matrixmaterial packed within a mold.
 30. The method of claim 29, wherein saidone or more pieces of sheet-form extracellular matrix material arecompressed within the mold.
 31. The method of claim 28, wherein saiddrying occurs after the molded construct has been removed from a mold.32. A medical graft product for sealing an opening in a bodily organ orvessel, the medical graft product comprising: an elongate molded graftbody; said elongate graft body including at least one generally conicallongitudinal segment configured to lodge within and fill the opening;said longitudinal segment comprising one or more pieces of compactedsheet-form collagenous matrix material defining contacting layerportions of the sheet-form collagenous matrix material; and wherein saidcontacting layer portions of matrix material are sufficientlydehydrothermally bonded to one another to provide said longitudinalsegment as a substantially unitary structure.